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abstract = {The requirement for the B-cell transcription factor OCT2 (octamer-binding protein 2, encoded by Pou2f2) in germinal center B cells has proved controversial. Here, we report that germinal center B cells are formed normally after depletion of OCT2 in a conditional knockout mouse, but their proliferation is reduced and in vivo differentiation to antibody-secreting plasma cells is blocked. This finding led us to examine the role of OCT2 in germinal center-derived lymphomas. shRNA knockdown showed that almost all diffuse large B-cell lymphoma (DLBCL) cell lines are addicted to the expression of OCT2 and its coactivator OCA-B. Genome-wide chromatin immunoprecipitation (ChIP) analysis and gene-expression profiling revealed the broad transcriptional program regulated by OCT2 that includes the expression of STAT3, IL-10, ELL2, XBP1, MYC, TERT, and ADA. Importantly, genetic alteration of OCT2 is not a requirement for cellular addiction in DLBCL. However, we detected amplifications of the POU2F2 locus in DLBCL tumor biopsies and a recurrent mutation of threonine 223 in the DNA-binding domain of OCT2. This neomorphic mutation subtly alters the DNA-binding preference of OCT2, leading to the transactivation of noncanonical target genes including HIF1a and FCRL3 Finally, by introducing mutations designed to disrupt the OCT2-OCA-B interface, we reveal a requirement for this protein-protein interface that ultimately might be exploited therapeutically. Our findings, combined with the predominantly B-cell-restricted expression of OCT2 and the absence of a systemic phenotype in our knockout mice, suggest that an OCT2-targeted therapeutic strategy would be efficacious in both major subtypes of DLBCL while avoiding systemic toxicity.},

langid = {english},

pmcid = {PMC4833274},

}

@article{melznerBiallelicMutationSOCS12005a,

doi = {10.1182/blood-2011-07-367532},

abstract = {In addition to its proapoptotic function, caspase-8 is also important for several other processes, including suppressing necroptosis, cell migration, and immune cell survival. In the present study, we report that the loss of caspase-8 in B lymphocytes leads to B-cell malignancies and that the risk for these tumors is further enhanced in the absence of p53. We also report that deficiency of caspase-8 results in impaired cytokinesis and that casp8(-/-) lymphomas display remarkably elevated levels of chromosomal aberrations. Our data support an important role for caspase-8 in the maintenance of genomic integrity and highlight its tumor-suppressive function.},

langid = {english},

}

@article{venturuttiTBL1XR1MutationsDrive2020b,

abstract = {The most aggressive B cell lymphomas frequently manifest extranodal distribution and carry somatic mutations in the poorly characterized gene TBL1XR1. Here, we show that TBL1XR1 mutations skew the humoral immune response toward generating abnormal immature memory B cells (MB), while impairing plasma cell differentiation. At the molecular level, TBL1XR1 mutants co-opt SMRT/HDAC3 repressor complexes toward binding the MB cell transcription factor (TF) BACH2 at the expense of the germinal center (GC) TF BCL6, leading to pre-memory transcriptional reprogramming and cell-fate bias. Upon antigen recall, TBL1XR1 mutant MB cells fail to differentiate into plasma cells and instead preferentially reenter new GC reactions, providing evidence for a cyclic reentry lymphomagenesis mechanism. Ultimately, TBL1XR1 alterations lead to a striking extranodal immunoblastic lymphoma phenotype that mimics the human disease. Both human and murine lymphomas feature expanded MB-like cell populations, consistent with a MB-cell origin and delineating an unforeseen pathway for malignant transformation of the immune system.},

langid = {english},

pmcid = {PMC7384961},

}

@article{huNovelMissenseM206K2013b,

abstract = {Persistent STAT3 activation has been found in activated B-cell like diffuse large B cell tumors (DLBCL). To investigate whether genetic mutations play a role in aberrant STAT3 signaling in DLBCL, we bi-directionally sequenced all 24 exons of the STAT3 gene in DLBCL tumors (n{$\mkern1mu$}={$\mkern1mu$}40). We identified 2 novel point mutations in 2 separate (2/40; 5\%) patients at exon 7 and 24. Point mutation 2552G{$>$}A was a silent mutation in the stop codon. Another heterozygous mutation 857T{$>$}A encoded a methionine substitution by lysine at codon 206 (M206K) in the coiled-coil domain of STAT3. We performed site directed mutagenesis to mutate wild type (WT) STAT3α and STAT3β at codon 206 and constructed stable cell lines by lentiviral transfection of STAT3α(WT), STAT3α(M206K), STAT3β(WT) and STAT3β(M206K) plasmids. The mutation was found to increase STAT3 phosphorylation in STAT3α mutant cell lines with no effect on the STAT3β mutant cell line. Transcriptional activation was also increased in the STAT3α mutant cells compared with STAT3α WT cells as detected by a luciferase reporter assay. Moreover, STAT3α(M206K) mutant cells were resistant to JAK2 pathway inhibition compared to STAT3α WT cells. These results indicate that missense mutations in STAT3 increase signaling through the JAK/STAT pathway. JAK2 inhibitors may be useful in the patient with this STAT3 mutation as well as those with pathway activation by other mechanisms.},

langid = {english},

pmcid = {PMC3701620},

}

@article{floriHematopoieticOncoproteinFOXP12016,

doi = {10.1182/blood-2015-08-662635},

abstract = {Aberrant expression of the oncogenic transcription factor forkhead box protein 1 (FOXP1) is a common feature of diffuse large B-cell lymphoma (DLBCL). We have combined chromatin immunoprecipitation and gene expression profiling after FOXP1 depletion with functional screening to identify targets of FOXP1 contributing to tumor cell survival. We find that the sphingosine-1-phosphate receptor 2 (S1PR2) is repressed by FOXP1 in activated B-cell (ABC) and germinal center B-cell (GCB) DLBCL cell lines with aberrantly high FOXP1 levels; S1PR2 expression is further inversely correlated with FOXP1 expression in 3 patient cohorts. Ectopic expression of wild-type S1PR2, but not a point mutant incapable of activating downstream signaling pathways, induces apoptosis in DLBCL cells and restricts tumor growth in subcutaneous and orthotopic models of the disease. The proapoptotic effects of S1PR2 are phenocopied by ectopic expression of the small G protein Gα13 but are independent of AKT signaling. We further show that low S1PR2 expression is a strong negative prognosticator of patient survival, alone and especially in combination with high FOXP1 expression. The S1PR2 locus has previously been demonstrated to be recurrently mutated in GCB DLBCL; the transcriptional silencing of S1PR2 by FOXP1 represents an alternative mechanism leading to inactivation of this important hematopoietic tumor suppressor.},

langid = {english},

}

@article{ortega-molinaOncogenicRagGTPase2019b,

abstract = {The humoral immune response demands that B cells undergo a sudden anabolic shift and high cellular nutrient levels which are required to sustain the subsequent proliferative burst. Follicular lymphoma (FL) originates from B cells that have participated in the humoral response, and 15\% of FL samples harbor point, activating mutations in RRAGC, an essential activator of mTORC1 downstream of the sensing of cellular nutrients. The impact of recurrent RRAGC mutations in B cell function and lymphoma is unexplored. RRAGC mutations, targeted to the endogenous locus in mice, confer a partial insensitivity to nutrient deprivation, but strongly exacerbate B cell responses and accelerate lymphomagenesis, while creating a selective vulnerability to pharmacological inhibition of mTORC1. This moderate increase in nutrient signaling synergizes with paracrine cues from the supportive T cell microenvironment that activates B cells via the PI3K-Akt-mTORC1 axis. Hence, Rragc mutations sustain induced germinal centers and murine and human FL in the presence of decreased T cell help. Our results support a model in which activating mutations in the nutrient signaling pathway foster lymphomagenesis by corrupting a nutrient-dependent control over paracrine signals from the T cell microenvironment.},

langid = {english},

pmcid = {PMC6774795},

}

@article{thomasMutationalAnalysisIkappaBalpha2004,

abstract = {There are over a 100 driver gene mutations in patients with diffuse large B-cell lymphoma (DLBCL), but their clinical significance remains unclear. Here, we first analyzed the DLBCL dataset from the UK-based Haematological Malignancy Research Network. Patients were divided into high- and low-risk groups based on whether lymphoma progressed within 24~months. Genes showing significantly different frequencies between groups were selected. Survival data for patients with the selected mutant genes were analyzed. The results were validated using two other large databases to evaluate the relationship between the selected mutant genes and prognosis. The mutation frequencies of 11 genes (MYD88[L265P], SGK1, MPEG1, TP53, SPEN, NOTCH1, ETV6, TNFRSF14, MGA, CIITA, and PIM1) significantly differed between the high- and low-risk groups. The relationships between these mutant genes and patient survival were analyzed. Patients who harbored SGK1 (serum and glucocorticoid-inducible kinase 1) mutations exhibited the best prognosis. Most patients with SGK1 mutation are germinal center B-cell (GCB) subtype. Among patients with GCB DLBCL, those harboring SGK1 mutations exhibited better prognosis than those without SGK1 mutations. Most SGK1 mutations were single-base substitutions, primarily scattered throughout the catalytic domain-encoding region. Multiple SGK1 mutations were identified in a single patient. Thus, SGK1 mutations are a marker of good prognosis for DLBCL and occur predominantly in the GCB subtype of DLBCL. SGK1 mutation status can further stratify patients with GCB DLBCL into different prognostic subgroups.},

langid = {english},

pmcid = {PMC8894717},

}

@article{jingjingNovelMEF2CMutation2020,

abstract = {The proliferative burst of B lymphocytes is essential for antigen receptor repertoire diversification during the development and selective expansion of antigen-specific clones during immune responses. High proliferative activity inevitably promotes oncogenesis, the risk of which is further elevated in B lymphocytes by endogenous gene rearrangement and somatic mutations. However, B-cell-derived cancers are rare, perhaps owing to putative intrinsic tumor-suppressive mechanisms. We show that c-MYC facilitates B-cell proliferation as a protumorigenic driver and unexpectedly coengages counteracting tumor suppression through its downstream factor TFAP4. TFAP4 is mutated in human lymphoid malignancies, particularly in {$>$}10\% of Burkitt lymphomas, and reduced TFAP4 expression was associated with poor survival of patients with MYC-high B-cell acute lymphoblastic leukemia. In mice, insufficient TFAP4 expression accelerated c-MYC-driven transformation of B cells. Mechanistically, c-MYC suppresses the stemness of developing B cells by inducing TFAP4 and restricting self-renewal of proliferating B cells. Thus, the pursuant transcription factor cascade functions as a tumor suppressor module that safeguards against the transformation of developing B cells.},

langid = {english},

pmcid = {PMC8678995},

}

@article{ohayreInactivatingMutationsGNA132016,

abstract = {G proteins and their cognate G protein-coupled receptors (GPCRs) function as critical signal transduction molecules that regulate cell survival, proliferation, motility and differentiation. The aberrant expression and/or function of these molecules have been linked to the growth, progression and metastasis of various cancers. As such, the analysis of mutations in the genes encoding GPCRs, G proteins and their downstream targets provides important clues regarding how these signaling cascades contribute to malignancy. Recent genome-wide sequencing efforts have unveiled the presence of frequent mutations in GNA13, the gene encoding the G protein Gα13, in Burkitt's lymphoma and diffuse large B-cell lymphoma (DLBCL). We found that mutations in the downstream target of Gα13, RhoA, are also present in Burkitt's lymphoma and DLBCL. By multiple complementary approaches, we now show that that these cancer-specific GNA13 and RHOA mutations are inhibitory in nature, and that the expression of wild-type Gα13 in B-cell lymphoma cells with mutant GNA13 has limited impact in vitro but results in a remarkable growth inhibition in vivo. Thus, although Gα13 and RhoA activity has previously been linked to cellular transformation and metastatic potential of epithelial cancers, our findings support a tumor suppressive role for Gα13 and RhoA in Burkitt's lymphoma and DLBCL.},

langid = {english},

pmcid = {PMC4885800},

}

@article{barisicARID1AOrchestratesSWI2024,

abstract = {Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma subtype characterized by both biological and clinical heterogeneity. In refractory cases, complete response/complete response unconfirmed rates in salvage therapy remain low. We performed whole-exome sequencing of DLBCL in a discovery cohort comprising 26 good and nine poor prognosis cases. After candidate genes were identified, prognoses were examined in 85 individuals in the DLBCL validation cohort. In the discovery cohort, five patients in the poor prognosis group harbored both a TP53 mutation and 17p deletion. Sixteen mutations were identified in OSBPL10 in nine patients in the good prognosis group, but none in the poor prognosis group. In the validation cohort, TP53 mutations and TP53 deletions were confirmed to be poor prognostic factors for overall survival (OS) (P = 0.016) and progression-free survival (PFS) (P = 0.023) only when both aberrations co-existed. OSBPL10 mutations were validated as prognostic markers for excellent OS (P = 0.037) and PFS (P = 0.041). Significant differences in OS and PFS were observed when patients were stratified into three groups-OSBPL10 mutation (best prognosis), the coexistence of both TP53 mutation and TP53 deletion (poorest prognosis), and others. In this study, the presence of both TP53 mutation and 17p/TP53 deletion, but not the individual variants, was associated with poor prognosis in DLBCL patients after treatment with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) or similar regimens. We also identified OSBPL10 mutation as a marker for patients with excellent prognosis in the R-CHOP era.},

langid = {english},

pmcid = {PMC5929408},

}

@article{christieCMYCTranslocation142008,

abstract = {Despite regulating overlapping gene enhancers and pathways, CREBBP and KMT2D mutations recurrently co-occur in germinal center (GC) B cell-derived lymphomas, suggesting potential oncogenic cooperation. Herein, we report that combined haploinsufficiency of Crebbp and Kmt2d induces a more severe mouse lymphoma phenotype (vs either allele alone) and unexpectedly confers an immune evasive microenvironment manifesting as CD8+ T-cell exhaustion and reduced infiltration. This is linked to profound repression of immune synapse genes that mediate crosstalk with T-cells, resulting in aberrant GC B cell fate decisions. From the epigenetic perspective, we observe interaction and mutually dependent binding and function of CREBBP and KMT2D on chromatin. Their combined deficiency preferentially impairs activation of immune synapse-responsive super-enhancers, pointing to a particular dependency for both co-activators at these specialized regulatory elements. Together, our data provide an example where chromatin modifier mutations cooperatively shape and induce an immune-evasive microenvironment to facilitate lymphomagenesis.},

langid = {english},

pmcid = {PMC10991284},

}

@article{merirantaDisruptionKLHL6Fuels2024,

issn = {2643-3249},

doi = {10.1158/2643-3230.BCD-23-0182},

abstract = {Pathomechanisms that activate oncogenic B-cell receptor (BCR) signaling in diffuse large B-cell lymphoma (DLBCL), are largely unknown. Kelch-like family member 6 (KLHL6) encoding a substrate-adapter for Cullin-3-RING E3 ubiquitin-ligase (CRL) with poorly established targets is recurrently mutated in DLBCL. By applying high-throughput protein interactome screens and functional characterization, we discovered that KLHL6 regulates BCR by targeting its signaling subunits CD79A and CD79B. Loss of physiological KLHL6 expression pattern was frequent among the MCD/C5-like activated B-cell DLBCLs and was associated with higher CD79B levels and dismal outcome. Mutations in the BTB domain of KLHL6 disrupted its localization and heterodimerization, and increased surface BCR levels and signaling, whereas Kelch domain mutants had the opposite effect. Malfunctions of KLHL6 mutants extended beyond proximal BCR signaling with distinct phenotypes from KLHL6 silencing. Collectively, our findings uncover how recurrent mutations in KLHL6 alter BCR signaling and induce actionable phenotypic characteristics in DLBCL.},

}

@article{choiRegulationCellReceptordependent2020,

abstract = {The KLHL14 gene acquires frequent inactivating mutations in mature B cell malignancies, especially in the MYD88L265P, CD79B mutant (MCD) genetic subtype of diffuse large B cell lymphoma (DLBCL), which relies on B cell receptor (BCR) signaling for survival. However, the pathogenic role of KLHL14 in DLBCL and its molecular function are largely unknown. Here, we report that KLHL14 is in close proximity to the BCR in the endoplasmic reticulum of MCD cell line models and promotes the turnover of immature glycoforms of BCR subunits, reducing total cellular BCR levels. Loss of KLHL14 confers relative resistance to the Bruton tyrosine kinase (BTK) inhibitor ibrutinib and promotes assembly of the MYD88-TLR9-BCR (My-T-BCR) supercomplex, which initiates prosurvival NF-κB activation. Consequently, KLHL14 inactivation allows MCD cells to maintain NF-κB signaling in the presence of ibrutinib. These findings reinforce the central role of My-T-BCR-dependent NF-κB signaling in MCD DLBCL and suggest that the genetic status of KLHL14 should be considered in clinical trials testing inhibitors of BTK and BCR signaling mediators in DLBCL.},

langid = {english},

pmcid = {PMC7084139},

}

@article{hodkinsonBiomarkersResponseIbrutinib2021,

abstract = {We analyzed potential biomarkers of response to ibrutinib plus nivolumab in biopsies from patients with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and Richter's transformation (RT) from the LYM1002 phase I/IIa study, using programmed death ligand 1 (PD-L1) immunohistochemistry, whole exome sequencing (WES), and gene expression profiling (GEP). In DLBCL, PD-L1 elevation was more frequent in responders versus nonresponders (5/8 [62.5\%] vs. 3/16 [18.8\%]; p\,=\,0.065; complete response 37.5\% vs. 0\%; p\,=\,0.028). Overall response rates for patients with WES and GEP data, respectively, were: DLBCL (38.5\% and 29.6\%); FL (46.2\% and 43.5\%); RT (76.5\% and 81.3\%). In DLBCL, WES analyses demonstrated that mutations in RNF213 (40.0\% vs. 6.2\%; p\,=\,0.055), KLHL14 (30.0\% vs. 0\%; p\,=\,0.046), and LRP1B (30.0\% vs. 6.2\%; p\,=\,0.264) were more frequent in responders. No responders had mutations in EBF1, ADAMTS20, AKAP9, TP53, MYD88, or TNFRSF14, while the frequency of these mutations in nonresponders ranged from 12.5\% to 18.8\%. In FL and RT, genes with different mutation frequencies in responders versus nonresponders were: BCL2 (75.0\% vs. 28.6\%; p\,=\,0.047) and ROS1 (0\% vs. 50.0\%; p\,=\,0.044), respectively. Per GEP, the most upregulated genes in responders were LEF1 and BTLA (overall), and CRTAM (germinal center B-cell-like DLBCL). Enriched pathways were related to immune activation in responders and resistance-associated proliferation/replication in nonresponders. This preliminary work may help to generate hypotheses regarding genetically defined subsets of DLBCL, FL, and RT patients most likely to benefit from ibrutinib plus nivolumab.},

langid = {english},

pmcid = {PMC7723809},

}

@article{saffieFBXW7TriggersDegradation2020b,

abstract = {Mature B-cell neoplasms are the fifth most common neoplasm. Due to significant heterogeneity at the clinical and genetic levels, current therapies for these cancers fail to provide long-term cures. The clinical success of proteasome inhibition for the treatment of multiple myeloma and B-cell lymphomas has made the ubiquitin pathway an important emerging therapeutic target. In this study, we assessed the role of the E3 ligase FBXW7 in mature B-cell neoplasms. FBXW7 targeted the frequently inactivated tumor suppressor KMT2D for protein degradation, subsequently regulating gene expression signatures related to oxidative phosphorylation (OxPhos). Loss of FBXW7 inhibited diffuse large B-cell lymphoma cell growth and further sensitized cells to OxPhos inhibition. These data elucidate a novel mechanism of regulation of KMT2D levels by the ubiquitin pathway and uncover a role of FBXW7 in regulating oxidative phosphorylation in B-cell malignancies. SIGNIFICANCE: These findings characterize FBXW7 as a prosurvival factor in B-cell lymphoma via degradation of the chromatin modifier KMT2D.},

langid = {english},

pmcid = {PMC7417195},

}

@article{schneiderFBXO11InactivationLeads2016b,

abstract = {The BCL6 proto-oncogene encodes a transcriptional repressor that is required for the germinal center (GC) reaction and is implicated in lymphomagenesis. BCL6 protein stability is regulated by F-box protein 11 (FBXO11)-mediated ubiquitination and degradation, which is impaired in ∼6\% of diffuse large B-cell lymphomas that carry inactivating genetic alterations targeting the FBXO11 gene. In order to investigate the role of FBXO11 in vivo, we analyzed GC-specific FBXO11 knockout mice. FBXO11 reduction or loss led to an increased number of GC B cells, to an altered ratio of GC dark zone to light zone cells, and to higher levels of BCL6 protein in GC B cells. B-cell receptor-mediated degradation of BCL6 was reduced in the absence of FBXO11, suggesting that FBXO11 contributes to the physiologic downregulation of BCL6 at the end of the GC reaction. Finally, FBXO11 inactivation was associated with the development of lymphoproliferative disorders in mice.},

langid = {english},

pmcid = {PMC9709922},

}

doi = {10.1186/s12943-021-01437-0},

langid = {english},

pmcid = {PMC8520256},

}

@article{campos-martinClinicalDiagnosticRelevance2017,

url = {https://haematologica.org/article/view/8174},

urldate = {2024-07-24},

issue = {8},

}

@article{ennishiTMEM30ALossoffunctionMutations2020b,

abstract = {BACKGROUND: The eukaryotic translation elongation factor 1A1 (EEF1A1) participates in protein translation and has been reported to be involved in tumor progression such as hepatocellular carcinoma. Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy in adults. In the present study, we aimed to detect the expression of EEF1A1 in DLBCL and to analyze its relationship with prognosis. METHODS: We reviewed medical records of DLBCL patients in our hospital and evaluated their expression level of EEF1A1 in tumor tissues using immunohistochemical (IHC) assay. The Chi-square method was used for correlation analysis. The Kaplan-Meier method with Log rank test was used for univariate analysis. Cox proportional hazards model was used for multivariate analysis. Cellular and mice models were introduced to validate its oncogenic role. RESULTS: EEF1A1 expression in tumor cells was higher in certain DLBCL cases. Patients with higher EEF1A1 expression were more likely to have advanced tumor stage and poorer 5-year overall survival (OS) rates. EEF1A1 expression in tumor cells was an independent risk predictor for OS (P {$<$} 0.05). Cellular assays demonstrated that EEF1A1-shRNA significantly inhibited lymphoma cell proliferation. The study of xenografts further verified the effect of EEF1A1-shRNA on suppressing tumor growth in vivo. CONCLUSION: EEF1A1 positivity predicts short survival in DLBCL patients. For patients with higher EEF1A1 expression, more strategy such as anti-EEF1A1 antibody treatment should be developed.},

langid = {english},

pmcid = {PMC8559353},

}

@article{demirandaExomeSequencingReveals2014,

abstract = {Next-generation sequencing studies on diffuse large B-cell lymphomas (DLBCLs) have revealed novel targets of genetic aberrations but also high intercohort heterogeneity. Previous studies have suggested that the prevalence of disease subgroups and cytogenetic profiles differ between Western and Asian patients. To characterize the coding genome of Chinese DLBCL, we performed whole-exome sequencing of DNA derived from 31 tumors and respective peripheral blood samples. The mutation prevalence of B2M, CD70, DTX1, LYN, TMSB4X, and UBE2A was investigated in an additional 105 tumor samples. We discovered 11 novel targets of recurrent mutations in DLBCL that included functionally relevant genes such as LYN and TMSB4X. Additional genes were found mutated at high frequency (≥10\%) in the Chinese cohort including DTX1, which was the most prevalent mutation target in the Notch pathway. We furthermore demonstrated that mutations in DTX1 impair its function as a negative regulator of Notch. Novel and previous unappreciated targets of somatic mutations in DLBCL identified in this study support the existence of additional/alternative tumorigenic pathways in these tumors. The observed differences with previous reports might be explained by the genetic heterogeneity of DLBCL, the germline genetic makeup of Chinese individuals, and/or exposure to distinct etiological agents.},

langid = {english},

pmcid = {PMC4199956},

}

@article{merirantaDeltex1MutationsPredict2017b,

doi = {10.3324/haematol.2016.157495},

langid = {english},

pmcid = {PMC5477623},

}

@article{jardinDiffuseLargeBcell2010a,

doi = {10.1182/blood-2009-10-247122},

abstract = {Genomic alterations play a crucial role in the development and progression of diffuse large B-cell lymphomas (DLBCLs). We determined gene copy number alterations (GCNAs) of TP53, CDKN2A, CDKN1B, BCL2, MYC, REL, and RB1 with a single polymerase chain reaction (PCR) assay (quantitative multiplex PCR of short fragments [QMPSF]) in a cohort of 114 patients with DLBCL to assess their prognostic value and relationship with the gene expression profile. Losses of TP53 and CDKN2A, observed in 8\% and 35\% of patients, respectively, were significantly associated with a shorter survival after rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) treatment, independently of the International Prognostic Index and of the cell of origin. Analysis of the 9p21 genomic region indicated that transcripts encoding p14ARF and p16INK4A were both disrupted in most patients with CDKN2A deletion. These patients predominantly had an activated B-cell profile and showed a specific gene expression signature, characterized by dysregulation of the RB/E2F pathway, activation of cellular metabolism, and decreased immune and inflammatory responses. These features may constitute the molecular basis sustaining the unfavorable outcome and chemoresistance of this DLBCL subgroup. Detection of TP53 and CDKN2A loss by QMPSF is a powerful tool that could be used for patient stratification in future clinical trials.},

langid = {english},

}

@article{zhaoExpressionPrognosticValue2016,

abstract = {INTRODUCTION: Primary testicular diffuse large B-cell lymphoma (PT-DLBCL) is a rare and aggressive form of mature B-cell lymphoma commonly found in elder males, but its genetic features are poorly understood. In this study, we had performed target-sequencing of 360 lymphoma-related genes on 76 PT-DLBCL patients with a median age of 65 (33-89). Our data provide a comprehensive understanding of the landscape of mutations in a small subset of PT-DLBCL. METHODS: A total of 76 PT-DLBCL patients were sequenced, and their clinical data and follow-up data were collected. The relationship between mutated genes, clinical data and prognosis and survival of PT-DLBCL patients was retrospectively analyzed by statistical software. RESULTS: We observed a median of 15 protein-altering variants per patient in our data and was identified recurrent oncogenic mutations of 360 lymphoma-related genes involved in PT-DLBCL, including PIM1 (74\%), MYD88 (50\%), KMT2D (38\%), KMT2C (34\%), BTG2 (34\%), TBL1XR1 (34\%) and ETV6 (24\%). Compared with classic DLBCL, PT-DLBCL showed an increased mutation frequency of PIM1, MYD88, BTG2, while NOTCH1 appeared exclusive mutated with PIM1, MSH3 and ETV6. Cox risk model regression analysis showed that age ≥60 years, IPI 3-5 points, BTG2 gene mutation and extranodal organ invasion suggested poor prognosis. Finally, we constructed an OS predict model of PT-DLBCL patients using above factors with a high accuracy. CONCLUSION: In conclusion, our results revealed genomic characterization of PT-DLBCL, and the mutation of BTG2 was an independent factor predicting a poor prognosis.},

langid = {english},

pmcid = {PMC8923029},

}

@article{bonatoNFKBIEMutationsAre2024,

abstract = {Loss-of-function mutations in NFKBIE, which encodes for the NF-κB inhibitor IκBε, are frequent in chronic lymphocytic leukemia (CLL) and certain other B-cell malignancies and have been associated with accelerated disease progression and inferior responses to chemotherapy. Using in vitro and in vivo murine models and primary patient samples, we now show that NFKBIE-mutated CLL cells are selected by microenvironmental signals that activate the NF-κB pathway and induce alterations within the tumor microenvironment that can allow for immune escape, including expansion of CD8+ T-cells with an exhausted phenotype and increased PD-L1 expression on the malignant B-cells. Consistent with the latter observations, we find increased expression of exhaustion markers on T-cells from patients with NFKBIE-mutated CLL. In addition, we show that NFKBIE-mutated murine CLL cells display selective resistance to ibrutinib and report inferior outcomes to ibrutinib treatment in NFKBIE-mutated CLL patients. These findings suggest that NFKBIE mutations can contribute to CLL progression through multiple mechanisms, including a bidirectional crosstalk with the microenvironment and reduced sensitivity to BTK inhibitor treatment.},

langid = {english},

pmcid = {PMC11216988},

}

@article{fanComprehensiveCharacterizationDriver2020b,

abstract = {Diffuse large B cell lymphoma (DLBCL) is the most common hematological malignancy and is one of the most frequent non-Hodgkin lymphomas. Large-scale genomic studies have defined genetic drivers of DLBCL and their association with functional and clinical outcomes. However, the lymphomagenesis of DLBCL is yet to be fully understood. In the present study, four computational tools OncodriveFM, OncodriveCLUST, integrated Cancer Genome Score and Driver Genes and Pathways were used to detect driver genes and driver pathways involved in DLBCL. The aforementioned tools were also used to perform an integrative investigation of driver genes, including co-expression network, protein-protein interaction, copy number variation and survival analyses. The present study identified 208 driver genes and 31 driver pathways in DLBCL. IGLL5, MLL2, BTG2, B2M, PIM1, CARD11 were the top five frequently mutated genes in DLBCL. NOTCH3, LAMC1, COL4A1, PDGFRB and KDR were the 5 hub genes in the blue module that were associated with patient age. TP53, MYC, EGFR, PTEN, IL6, STAT3, MAPK8, TNF and CDH1 were at the core of the protein-protein interaction network. PRDM1, CDKN2A, CDKN2B, TNFAIP3, RSPO3 were the top five frequently deleted driver genes in DLBCL, while ACTB, BTG2, PLET1, CARD11, DIXDC1 were the top five frequently amplified driver genes in DLBCL. High EIF3B, MLH1, PPP1CA and RECQL4 expression was associated with decreased overall survival rate of patients with DLBCL. High XPO1 and LYN expression were associated with increased overall survival rate of patients with DLBCL. The present study improves the understanding of the biological processes and pathways involved in lymphomagenesis. The driver genes, EIF3B, MLH1, PPP1CA, RECQL4, XPO1 and LYN, pave the way for developing prognostic biomarkers and new therapeutic strategies for DLBCL.},

langid = {english},

pmcid = {PMC7285964},

}

@article{lunningMutationChromatinModifiers2015b,

abstract = {Subtypes of non-Hodgkin's lymphomas align with different stages of B-cell development. Germinal center B-cell (GCB)-like diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and Burkitt's lymphoma (BL) each share molecular similarities with normal GCB cells. Recent next-generation sequencing studies have gained insight into the genetic etiology of these malignancies and revealed a high frequency of mutations within genes encoding proteins that modifying chromatin. These include activating and inactivating mutations of genes that perform post-translational modification of histones and organize chromatin structure. Here, we discuss the function of histone acetyltransferases (CREBBP, EP300), histone methyltransferases (KDM2C/D, EZH2) and regulators of higher order chromatin structure (HIST1H1C/D/E, ARID1A and SMARCA4) that have been reported to be mutated in ⩾5\% of DLBCL, FL or BL. Mutations of these genes are an emerging hallmark of lymphomas with GCB-cell origins, and likely represent the next generation of therapeutic targets for these malignancies.},

langid = {english},

pmcid = {PMC4635197},

}

@article{witjesPrevalenceCytoplasmicActin2020b,

abstract = {Mutations in actins have been linked to several developmental diseases. Their occurrence across different cancers has, however, not been investigated. Using the cBioPortal database we show that human actins are infrequently mutated in patient samples of various cancers types. Nevertheless, ranking these studies by mutational frequency suggest that some have a higher percentage of patients with ACTB and ACTG1 mutations. Within studies on hematological cancers, mutations in ACTB and ACTG1 are associated with lymphoid cancers since none have currently been reported in myeloid cancers. Within the different types of lymphoid cancers ACTB mutations are most frequent in diffuse large B-cell lymphoma (DLBCL) and ACTG1 mutations in multiple myeloma. We mapped the ACTB and ACTG1 mutations found in these two cancer types on the 3D-structure of actin showing they are in regions important for actin polymer formation or binding to myosin. The potential effects of the mutations on actin properties imply that mutations in cytoplasmic actins deserve dedicated research in DLBCL and multiple myeloma.},

langid = {english},

pmcid = {PMC7247664},

}

@article{delageBTG1InactivationDrives2023a,

doi = {10.1182/blood.2022016943},

abstract = {Understanding the functional role of mutated genes in cancer is required to translate the findings of cancer genomics into therapeutic improvement. BTG1 is recurrently mutated in the MCD/C5 subtype of diffuse large B-cell lymphoma (DLBCL), which is associated with extranodal dissemination. Here, we provide evidence that Btg1 knock out accelerates the development of a lethal lymphoproliferative disease driven by Bcl2 overexpression. Furthermore, we show that the scaffolding protein BCAR1 is a BTG1 partner. Moreover, after BTG1 deletion or expression of BTG1 mutations observed in patients with DLBCL, the overactivation of the BCAR1-RAC1 pathway confers increased migration ability in~vitro and in~vivo. These modifications are targetable with the SRC inhibitor dasatinib, which opens novel therapeutic opportunities in BTG1 mutated DLBCL.},

langid = {english},

}

@article{mlynarczykBTG1MutationYields2023b,

journaltitle = {Leukemia},

shortjournal = {Leukemia},

pages = {1--14},

}

@article{phelanBCL10MutantsArchitects2022,

doi = {10.1158/2159-8290.CD-22-0614},

abstract = {BCL10, a key activator of NF-κB downstream of oncogenic B-cell receptor signaling, is mutated in nearly 40\% of the BN2/C1 genetic subtype of diffuse large B-cell lymphoma, but how these mutations function to augment signaling and their relevance to targeted precision medicine agents remains unclear. In this issue of Cancer Discovery, Xia and colleagues demonstrate distinct mechanisms of oncogenic signaling regulation and therapeutic vulnerabilities among different recurrent BCL10 mutations. See related article by Xia et al., p. 1922 (1).},

langid = {english},

}

@article{xiaBCL10MutationsDefine2022,

abstract = {Activated B cell-like diffuse large B-cell lymphomas (ABC-DLBCL) have unfavorable outcomes and chronic activation of CARD11-BCL10-MALT1 (CBM) signal amplification complexes that form due to polymerization of BCL10 subunits, which is affected by recurrent somatic mutations in ABC-DLBCLs. Herein, we show that BCL10 mutants fall into at least two functionally distinct classes: missense mutations of the BCL10 CARD domain and truncation of its C-terminal tail. Truncating mutations abrogated a motif through which MALT1 inhibits BCL10 polymerization, trapping MALT1 in its activated filament-bound state. CARD missense mutations enhanced BCL10 filament formation, forming glutamine network structures that stabilize BCL10 filaments. Mutant forms of BCL10 were less dependent on upstream CARD11 activation and thus manifested resistance to BTK inhibitors, whereas BCL10 truncating but not CARD mutants were hypersensitive to MALT1 inhibitors. Therefore, BCL10 mutations are potential biomarkers for BTK inhibitor resistance in ABC-DLBCL, and further precision can be achieved by selecting therapy based on specific biochemical effects of distinct mutation classes. SIGNIFICANCE: ABC-DLBCLs feature frequent mutations of signaling mediators that converge on the CBM complex. We use structure-function approaches to reveal that BCL10 mutations fall into two distinct biochemical classes. Both classes confer resistance to BTK inhibitors, whereas BCL10 truncations confer hyperresponsiveness to MALT1 inhibitors, providing a road map for precision therapies in ABC-DLBCLs. See related commentary by Phelan and Oellerich, p. 1844. This article is highlighted in the In This Issue feature, p. 1825.},

langid = {english},

pmcid = {PMC9357155},

}

@article{dengSMARCA4HaploinsufficientCell2024,

abstract = {SMARCA4 encodes one of two mutually exclusive ATPase subunits in the BRG/BRM associated factor (BAF) complex that is recruited by transcription factors (TFs) to drive chromatin accessibility and transcriptional activation. SMARCA4 is among the most recurrently mutated genes in human cancer, including ∼30\% of germinal center (GC)-derived Burkitt lymphomas. In mice, GC-specific Smarca4 haploinsufficiency cooperated with MYC over-expression to drive lymphomagenesis. Furthermore, monoallelic Smarca4 deletion drove GC hyperplasia with centroblast polarization via significantly increased rates of centrocyte recycling to the dark zone. Mechanistically, Smarca4 loss reduced the activity of TFs that are activated in centrocytes to drive GC-exit, including SPI1 (PU.1), IRF family, and NF-κB. Loss of activity for these factors phenocopied aberrant BCL6 activity within murine centrocytes and human Burkitt lymphoma cells. SMARCA4 therefore facilitates chromatin accessibility for TFs that shape centrocyte trajectories, and loss of fine-control of these programs biases toward centroblast cell-fate, GC hyperplasia and lymphoma.},

langid = {english},

pmcid = {PMC11003852},

}

@article{challa-malladiCombinedGeneticInactivationa,

title = {Combined {{Genetic Inactivation}} of \&beta;2-{{Microglobulin}} and {{CD58 Reveals Frequent Escape}} from {{Immune Recognition}} in {{Diffuse Large B Cell Lymphoma}}},

author = {Challa-Malladi, Madhavi and Lieu, Yen K and Califano, Olivia and Holmes, Antony B and Bhagat, Govind and Murty, Vundavalli V and Dominguez-Sola, David and Pasqualucci, Laura and Dalla-Favera, Riccardo},

journaltitle = {Cancer Cell},

}

@article{nieGenomewideCRISPRScreens2021b,

abstract = {Diffuse large B-cell lymphoma (DLBCL) is the most common type of aggressive lymphoid malignancy and a highly heterogeneous disease. In this study, we performed whole-genome and transcriptome sequencing, and a genome-wide CRISPR-Cas9-knockout screen to study an activated B-cell-like DLBCL cell line (RC-K8). We identified a distinct pattern of genetic essentialities in RC-K8, including a dependency on CREBBP and MDM2. The dependency on CREBBP is associated with a balanced translocation involving EP300, which results in a truncated form of the protein that lacks the critical histone acetyltransferase (HAT) domain. The synthetic lethal interaction between CREBBP and EP300 genes, two frequently mutated epigenetic modulators in B-cell lymphoma, was further validated in the previously published CRISPR-Cas9 screens and inhibitor assays. Our study suggests that integration of the unbiased functional screen results with genomic and transcriptomic data can identify both common and unique druggable vulnerabilities in DLBCL and histone acetyltransferases inhibition could be a therapeutic option for CREBBP or EP300 mutated cases.},

langid = {english},

pmcid = {PMC8080727},

}

@article{veazeyCARM1InhibitionReduces2020b,

abstract = {Somatic mutations affecting CREBBP and EP300 are a hallmark of diffuse large B-cell lymphoma (DLBCL). These mutations are frequently monoallelic, within the histone acetyltransferase (HAT) domain and usually mutually exclusive, suggesting that they might affect a common pathway, and their residual WT expression is required for cell survival. Using in vitro and in vivo models, we found that inhibition of CARM1 activity (CARM1i) slows DLBCL growth, and that the levels of sensitivity are positively correlated with the CREBBP/EP300 mutation load. Conversely, treatment of DLBCLs that do not have CREBBP/EP300 mutations with CARM1i and a CBP/p300 inhibitor revealed a strong synergistic effect. Our mechanistic data show that CARM1i further reduces the HAT activity of CBP genome wide and downregulates CBP-target genes in DLBCL cells, resulting in a synthetic lethality that leverages the mutational status of CREBBP/EP300 as a biomarker for the use of small-molecule inhibitors of CARM1 in DLBCL and other cancers.},

langid = {english},

pmcid = {PMC7688486},

}

@article{scholzeCombinedEZH2Bcl22020b,

abstract = {Next-generation sequencing of follicular lymphoma and diffuse-large B-cell lymphoma has revealed frequent somatic, heterozygous Y641 mutations in the histone methyltransferase EZH2. Heterozygosity and the presence of equal quantities of both mutant and wild-type mRNA and expressed protein suggest a dominant mode of action. Surprisingly, B-cell lymphoma cell lines and lymphoma samples harboring heterozygous EZH2(Y641) mutations have increased levels of histone H3 Lys-27-specific trimethylation (H3K27me3). Expression of EZH2(Y641F/N) mutants in cells with EZH2(WT) resulted in an increase of H3K27me3 levels in vivo. Structural modeling of EZH2(Y641) mutants suggests a "Tyr/Phe switch" model whereby structurally neutral, nontyrosine residues at position 641 would decrease affinity for unmethylated and monomethylated H3K27 substrates and potentially favor trimethylation. We demonstrate, using in vitro enzyme assays of reconstituted PRC2 complexes, that Y641 mutations result in a decrease in monomethylation and an increase in trimethylation activity of the enzyme relative to the wild-type enzyme. This represents the first example of a disease-associated gain-of-function mutation in a histone methyltransferase, whereby somatic EZH2 Y641 mutations in lymphoma act dominantly to increase, rather than decrease, histone methylation. The dominant mode of action suggests that allele-specific EZH2 inhibitors should be a future therapeutic strategy for this disease.},

langid = {english},

pmcid = {PMC3062411},

}

@article{hartmannHighlyRecurrentMutations2016b,

abstract = {T-cell/histiocyte-rich large B-cell lymphoma is a rare aggressive lymphoma showing histopathological overlap with nodular lymphocyte-predominant Hodgkin lymphoma. Despite differences in tumor microenvironment and clinical behavior, the tumor cells of both entities show remarkable similarities, suggesting that both lymphomas might represent a spectrum of the same disease. To address this issue, we investigated whether these entities share mutations. Ultra-deep targeted resequencing of six typical and 11 histopathological variants of nodular lymphocyte-predominant Hodgkin lymphoma, and nine cases of T-cell/histiocyte-rich large B-cell lymphoma revealed that genes recurrently mutated in nodular lymphocyte-predominant Hodgkin lymphoma are affected by mutations at similar frequencies in T-cell/histiocyte-rich large B-cell lymphoma. The most recurrently mutated genes were JUNB, DUSP2, SGK1, SOCS1 and CREBBP, which harbored mutations more frequently in T-cell/histiocyte-rich large B-cell lymphoma and the histopathological variants of nodular lymphocyte-predominant Hodgkin lymphoma than in its typical form. Mutations in JUNB, DUSP2, SGK1 and SOCS1 were highly enriched for somatic hypermutation hotspot sites, suggesting an important role of aberrant somatic hypermutation in the generation of these somatic mutations and thus in the pathogenesis of both lymphoma entities. Mutations in JUNB are generally rarely observed in malignant lymphomas and thus are relatively specific for nodular lymphocyte-predominant Hodgkin lymphoma and T-cell/histiocyte-rich large B-cell lymphoma at such high frequencies (5/17 and 5/9 cases with JUNB mutations, respectively). Taken together, the findings of the present study further support a close relationship between T-cell/histiocyte-rich large B-cell lymphoma and nodular lymphocyte-predominant Hodgkin lymphoma by showing that they share highly recurrent genetic lesions.},

langid = {english},

pmcid = {PMC6355500},

}

@article{wilsonEffectIbrutinibRCHOP2021b,

abstract = {In diffuse large B cell lymphoma (DLBCL), tumors belonging to the ABC but not GCB gene expression subgroup rely upon chronic active B cell receptor signaling for viability, a dependency that is targetable by ibrutinib. A phase III trial ("Phoenix;" ClinicalTrials.gov: NCT01855750) showed a survival benefit of ibrutinib addition to R-CHOP chemotherapy in younger patients with non-GCB DLBCL, but the molecular basis for this benefit was unclear. Analysis of biopsies from Phoenix trial patients revealed three previously characterized genetic subtypes of DLBCL: MCD, BN2, and N1. The 3-year event-free survival of younger patients (age ≤60 years) treated with ibrutinib plus R-CHOP was 100\% in the MCD and N1 subtypes while the survival of patients with these subtypes treated with R-CHOP alone was significantly inferior (42.9\% and 50\%, respectively). This work provides a mechanistic understanding of the benefit of ibrutinib addition to chemotherapy, supporting its use in younger patients with non-GCB DLBCL.},

langid = {english},

pmcid = {PMC8722194},

}

@article{flumannInducibleCd79bMutation2024,

abstract = {Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive lymphoma and constitutes a highly heterogenous disease. Recent comprehensive genomic profiling revealed the identity of numerous molecularly defined DLBCL subtypes, including a cluster which is characterized by recurrent aberrations in MYD88, CD79B, and BCL2, as well as various lesions promoting a block in plasma cell differentiation, including PRDM1, TBL1XR1, and SPIB. Here, we generated a series of autochthonous mouse models to mimic this DLBCL cluster and specifically focused on the impact of Cd79b mutations in this setting. We show that canonical Cd79b immunoreceptor tyrosine-based activation motif (ITAM) mutations do not accelerate Myd88- and BCL2-driven lymphomagenesis. Cd79b-mutant murine DLBCL were enriched for IgM surface expression, reminiscent of their human counterparts. Moreover, Cd79b-mutant lymphomas displayed a robust formation of cytoplasmic signaling complexes involving MYD88, CD79B, MALT1, and BTK. These~complexes were disrupted upon pharmacological BTK inhibition. The BTK inhibitor-mediated disruption of these signaling complexes translated into a selective ibrutinib sensitivity of lymphomas harboring combined Cd79b and Myd88 mutations. Altogether, this in-depth cross-species comparison provides a framework for the development of molecularly targeted therapeutic intervention strategies in DLBCL.},

langid = {english},

pmcid = {PMC10907402},

}

@article{mandatoAbstractA38Cd702022,

url = {https://doi.org/10.1158/2643-3249.LYMPHOMA22-A38},

urldate = {2024-06-09},

abstract = {Multiple immunomodulatory pathways shape the development of anti-tumor immune responses to lymphoid malignancies. We previously defined the recurrent genetic alterations in diffuse large B-cell lymphoma (DLBCL) and identified associated substructure and additional potential genetic bases for immune escape. CD70 was the most commonly perturbed immune response pathway component in our cohort of primary DLBCLs; alterations included inactivating mutations and copy loss. CD70 co-stimulation of CD27+ T cells induces antigen-dependent T-cell expansion and immune surveillance of normal and malignant B cells. Given the frequent co-association of CD70 alterations and BCL6 translocations in our DLBCL patient series, we assessed the consequences of Cd70 deficiency on Bcl6-driven lymphomagenesis in a murine model. We crossed previously generated Cd70−/- and Bcl6tg/+ mice to obtain Cd70−/−; Bcl6tg/+ animals. In our aging cohorts, Cd70−/−; Bcl6tg/+ mice developed significantly increased numbers of histopathologically confirmed DLBCLs at earlier timepoints, compared to Bcl6tg/+ animals. Both the Cd70−/−; Bcl6tg/+ and Bcl6tg/+ mice that were euthanized for symptoms exhibited massive splenomegaly and lymphomatous splenic infiltration. None of the wild-type (WT) and Cd70−/- animals developed lymphoma. To characterize potential differences in anti-tumor responses in Cd70−/−; Bcl6tg/+ versus Bcl6tg/+ mice, we harvested spleens from asymptomatic animals in each cohort at 6, 14 and 18 months (mo). Cd70−/−; Bcl6tg/+ mice exhibited significantly earlier onset splenomegaly than Bcl6tg/+ animals (both in comparison with WT mice). We performed single cell RNA sequencing of splenic cell suspensions from each murine cohort at the above-mentioned predetermined timepoints (6, 14 and 18 mo) and describe genotype-related changes in splenic CD8+ T-cell infiltration in this abstract. Our study revealed an age-related decline in the percentages of naive CD8+ T cells in all genotypes, with more striking and earlier changes in Cd70−/−; Bcl6tg/+ animals. Cd70−/−; Bcl6tg/+ and Bcl6tg/+ mice exhibited a selective and significant expansion of CD8+ cytotoxic T cells (CTLs), which expressed Gzmb and Prf1 and the exhaustion markers, Pdcd1, Lag3, Tigit, Tox and Tim3, and exhibited clonal expansion. At 6 mo, prior to splenic enlargement and the development of symptoms, CD8+ CTLs in Cd70−/−; Bcl6tg/+ animals expressed significantly higher levels of exhaustion markers than those in Bcl6tg/+ mice. Consistent with this finding, there was a more limited expansion and a subsequent contraction of these splenic CD8+ CTLs in Cd70−/−; Bcl6tg/+ mice, in comparison to Bcl6tg/+ animals. Taken together, these findings suggest that initial anti-tumor immune responses are less effective in Cd70−/−; Bcl6tg/+ mice than in Bcl6tg/+ animals and highlight the likely importance of CD70/CD27 co-stimulation in CD8+ T-cell response to Bcl6-driven DLBCL.Citation Format: Elisa Mandato, Eleonora Calabretta, Gali Bai, Li Song, Yanbo Sun, Vignesh Shanmugam, Julia Paczkowska, Il-Kyu Choi, Robert Redd, Ming Tang, Lee N Lawton, Donna Neuberg, Scott Rodig, Franziska Michor, Baochun Zhang, Margaret A Shipp. Cd70 genetic perturbation limits the development of an effective CD8+ T-cell immune response to Bcl6-driven diffuse large B-cell lymphoma [abstract]. In: Proceedings of the Third AACR International Meeting: Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2022 Jun 23-26; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2022;3(5\_Suppl):Abstract nr A38.},

}

@article{nieDualRoleCD702022b,

abstract = {BACKGROUND: CD70 is a costimulatory molecule that is transiently expressed on a small set of activated lymphocytes and is involved in T-cell-mediated immunity. However, the role of CD70 in B-cell malignancies remains controversial. METHODS: We investigated the clinical relevance of CD70 genetic alterations and its protein expression in two diffuse large B-cell lymphoma (DLBCL) cohorts with different ethnic backgrounds. We also performed transcriptomic analysis to explore the role of CD70 alterations in tumour microenvironment. We further tested the blockade of CD70 in combination with PD-L1 inhibitor in a murine lymphoma model. RESULTS: We showed that CD70 genetic aberrations occurred more frequently in the Chinese DLBCL cohort (56/233, 24.0\%) than in the Swedish cohort (9/84, 10.8\%), especially in those with concomitant hepatitis B virus (HBV) infection. The CD70 genetic changes in DLBCL resulted in a reduction/loss of protein expression and/or CD27 binding, which might impair T cell priming and were independently associated with poor overall survival. Paradoxically, we observed that over-expression of CD70 protein was also associated with a poor treatment response, as well as an advanced disease stage and EBV infection. More exhausted CD8+ T cells were furthermore identified in CD70 high-expression DLBCLs. Finally, in a murine lymphoma model, we demonstrated that blocking the CD70/CD27 and/or PD1/PD-L1 interactions could reduce CD70+ lymphoma growth in vivo, by directly impairing the tumour cell proliferation and rescuing the exhausted T cells. CONCLUSIONS: Our findings suggest that CD70 can play a role in either tumour suppression or oncogenesis in DLBCL, likely via distinct immune evasion mechanisms, that is, impairing T cell priming or inducing T cell exhaustion. Characterisation of specific dysfunction of CD70 in DLBCL may thus provide opportunities for the development of novel targeted immuno-therapeutic strategies.},

langid = {english},

pmcid = {PMC9722974},

}

@article{abateDistinctViralMutational2015a,

title = {Distinct {{Viral}} and {{Mutational Spectrum}} of {{Endemic Burkitt Lymphoma}}},

journaltitle = {PLoS Pathogens},

shortjournal = {PLoS Pathogens},

volume = {11},

}

@article{abrisquetaObservationInitialManagement2017,

url = {https://www.nature.com/articles/s41591-018-0243-z},

urldate = {2019-12-21},

abstract = {Molecular alterations in ctDNA of patients with mantle cell lymphoma uncovers mutations in SWI–SNF associated with resistance to ibrutinib and venetoclax combination and provide a rationale for restoring sensitivity through Bcl-xL inhibition.},

}

@article{ahmadiMYCMultipurposeOncogene2021,

url = {https://doi.org/10.1186/s13045-021-01111-4},

urldate = {2022-10-06},

abstract = {MYC oncogene is a transcription factor with a wide array of functions affecting cellular activities such as cell cycle, apoptosis, DNA damage response, and hematopoiesis. Due to the multi-functionality of MYC, its expression is regulated at multiple levels. Deregulation of this oncogene can give rise to a variety of cancers. In this review, MYC regulation and the mechanisms by which MYC adjusts cellular functions and its implication in hematologic malignancies are summarized. Further, we also discuss potential inhibitors of MYC that could be beneficial for treating hematologic malignancies.},

}

@article{ahmedGeneMutationsActionable2016,

doi = {10.18632/oncotarget.10716},

url = {http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=10716&pubmed-linkout=1},

urldate = {2019-12-21},

}

@article{akbariMegabasescaleMethylationPhasing2021,

url = {https://doi.org/10.1186/s13059-021-02283-5},

urldate = {2022-02-07},

abstract = {The ability of nanopore sequencing to simultaneously detect modified nucleotides while producing long reads makes it ideal for detecting and phasing allele-specific methylation. However, there is currently no complete software for detecting SNPs, phasing haplotypes, and mapping methylation to these from nanopore sequence data. Here, we present NanoMethPhase, a software tool to phase 5-methylcytosine from nanopore sequencing. We also present SNVoter, which can post-process nanopore SNV calls to improve accuracy in low coverage regions. Together, these tools can accurately detect allele-specific methylation genome-wide using nanopore sequence data with low coverage of about ten-fold redundancy.},

}

@article{akhoondiFBXW7HCDC4General2007,

url = {https://cancerres.aacrjournals.org/content/67/19/9006},

urldate = {2021-08-25},

abstract = {The ubiquitin-proteasome system is a major regulatory pathway of protein degradation and plays an important role in cellular division. Fbxw7 (or hCdc4), a member of the F-box family of proteins, which are substrate recognition components of the multisubunit ubiquitin ligase SCF (Skp1-Cdc53/Cullin-F-box-protein), has been shown to mediate the ubiquitin-dependent proteolysis of several oncoproteins including cyclin E1, c-Myc, c-Jun, and Notch. The oncogenic potential of Fbxw7 substrates, frequent allelic loss in human cancers, and demonstration that mutation of FBXW7 cooperates with p53 in mouse tumorigenesis have suggested that Fbxw7 could function as a tumor suppressor in human cancer. Here, we carry out an extensive genetic screen of primary tumors to evaluate the role of FBXW7 as a tumor suppressor in human tumorigenesis. Our results indicate that FBXW7 is inactivated by mutation in diverse human cancer types with an overall mutation frequency of ∼6\%. The highest mutation frequencies were found in tumors of the bile duct (cholangiocarcinomas, 35\%), blood (T-cell acute lymphocytic leukemia, 31\%), endometrium (9\%), colon (9\%), and stomach (6\%). Approximately 43\% of all mutations occur at two mutational “hotspots,” which alter Arg residues (Arg465 and Arg479) that are critical for substrate recognition. Furthermore, we show that Fbxw7Arg465 hotspot mutant can abrogate wild-type Fbxw7 function through a dominant negative mechanism. Our study is the first comprehensive screen of FBXW7 mutations in various human malignancies and shows that FBXW7 is a general tumor suppressor in human cancer. [Cancer Res 2007;67(19):9006–12]},

}

@article{alaggio5thEditionWorld2022,

abstract = {We herein present an overview of the upcoming 5th edition of the World Health Organization Classification of Haematolymphoid Tumours focussing on lymphoid neoplasms. Myeloid and histiocytic neoplasms will be presented in a separate accompanying article. Besides listing the entities of the classification, we highlight and explain changes from the revised 4th edition. These include reorganization of entities by a hierarchical system as is adopted throughout the 5th edition of the WHO classification of tumours of all organ systems, modification of nomenclature for some entities, revision of diagnostic criteria or subtypes, deletion of certain entities, and introduction of new entities, as well as inclusion of tumour-like lesions, mesenchymal lesions specific to lymph node and spleen, and germline predisposition syndromes associated with the lymphoid neoplasms.},

langid = {english},

pmcid = {PMC9214472},

}

@article{alarconHNRNPA2B1MediatorM6ADependent2015,

doi = {10.1016/j.cell.2015.08.011},

url = {https://www.cell.com/cell/abstract/S0092-8674(15)01024-7},

urldate = {2022-09-28},

}

@article{albuquerqueEnhancingKnowledgeDiscovery2017a,

abstract = {The field of cancer genomics has demonstrated the power of massively parallel sequencing techniques to inform on the genes and specific alterations that drive tumor onset and progression. Although large comprehensive sequence data sets continue to be made increasingly available, data analysis remains an ongoing challenge, particularly for laboratories lacking dedicated resources and bioinformatics expertise. To address this, we have produced a collection of Galaxy tools that represent many popular algorithms for detecting somatic genetic alterations from cancer genome and exome data. We developed new methods for parallelization of these tools within Galaxy to accelerate runtime and have demonstrated their usability and summarized their runtimes on multiple cloud service providers. Some tools represent extensions or refinement of existing toolkits to yield visualizations suited to cohort-wide cancer genomic analysis. For example, we present Oncocircos and Oncoprintplus, which generate data-rich summaries of exome-derived somatic mutation. Workflows that integrate these to achieve data integration and visualizations are demonstrated on a cohort of 96 diffuse large B-cell lymphomas and enabled the discovery of multiple candidate lymphoma-related genes. Our toolkit is available from our GitHub repository as Galaxy tool and dependency definitions and has been deployed using virtualization on multiple platforms including Docker.},

langid = {english},

pmcid = {PMC5437943},

}

@article{alcaideTargetedErrorsuppressedQuantification2017,

journaltitle = {Scientific reports},

volume = {7},

number = {1},

}

@article{alcaideUltrasensitiveDetectionCirculating2019,

doi = {10.1182/blood.2022018248},

url = {https://doi.org/10.1182/blood.2022018248},

urldate = {2024-01-19},

}

@article{algamalGeneSelectionMicroarray2018,

author = {Alix-Panabières, Catherine and Schwarzenbach, Heidi and Pantel, Klaus},

journaltitle = {Annual review of medicine},

volume = {63},

}

@article{alizadehDistinctTypesDiffuse2000,

journaltitle = {Nature},

volume = {403},

number = {6769},

}

@article{alizadehLymphochipSpecializedCDNA1999,

date = {1999},

journaltitle = {Cold Spring Harbor symposia on quantitative biology},

volume = {64},

}

@article{alizadehNovelClassificationHuman2001,

doi = {10.1002/path.889},

abstract = {As a result of progress on the human genome project, approximately 19 000 genes have been identified and tens of thousands more tentatively identified as partial fragments of genes termed expressed sequence tags (ESTs). Most of these genes are only partially characterized and the functions of the vast majority are as yet unknown. It is likely that many genes that might be useful for diagnosis and/or prognostication of human malignancies have yet to be recognized. The advent of cDNA microarray technology now allows the efficient measurement of expression for almost every gene in the human genome in a single overnight hybridization experiment. This genomic scale approach has begun to reveal novel molecular-based sub-classes of tumours in breast carcinoma, colon carcinoma, lymphoma, leukaemia, and melanoma. In several instances, gene microarray analysis has already identified genes that appear to be useful for predicting clinical behaviour. This review discusses some recent findings using gene microarray technology and describes how this and related technologies are likely to contribute to the emergence of novel molecular classifications of human malignancies.},

langid = {english},

}

@article{alizadehPredictionSurvivalDiffuse,

title = {Prediction of Survival in Diffuse Large {{B-cell}} Lymphoma Based on the Expression of 2 Genes Reflecting Tumor and Microenvironment},

}

@article{alkallasMultiomicAnalysisReveals2020,

urldate = {2021-06-01},

abstract = {The high background tumor mutation burden in cutaneous melanoma limits the ability to identify significantly mutated genes (SMGs) that drive this cancer. To address this, we performed a mutation significance study of over 1,000 melanoma exomes, combined with a multi-omic analysis of 470 cases from The Cancer Genome Atlas. We discovered several SMGs with co-occurring loss-of-heterozygosity and loss-of-function mutations, including PBRM1, PLXNC1 and PRKAR1A, which encodes a protein kinase A holoenzyme subunit. Deconvolution of bulk tumor transcriptomes into cancer, immune and stromal components revealed a melanoma-intrinsic oxidative phosphorylation signature associated with protein kinase A pathway alterations. We also identified SMGs on the X chromosome, including the RNA helicase DDX3X, whose loss-of-function mutations were exclusively observed in males. Finally, we found that tumor mutation burden and immune infiltration contain complementary information on survival of patients with melanoma. In summary, our multi-omic analysis provides insights into melanoma etiology and supports contribution of specific mutations to the sex bias observed in this cancer.},

issue = {6},

}

@article{AnalysisCirculatingTumor2001,

title = {Analysis of {{Circulating Tumor DNA}} in {{Plasma}} at {{Diagnosis}} and during {{Follow-Up}} of {{Lung Cancer Patients}}},

date = {2001-06},

}

@article{andersHTSeqPythonFramework2015,

url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7259945/},

urldate = {2022-09-28},

abstract = {RNA binding protein PCBP1 guards effector and antitumor T cell functions., Distinct lineages of T cells can act in response to various environmental cues to either drive or restrict immune-mediated pathology. Here, we identify the RNA binding protein, poly(C)-binding protein 1 (PCBP1) as an intracellular immune checkpoint that is up-regulated in activated T cells to prevent conversion of effector T (Teff) cells into regulatory T (Treg) cells, by restricting the expression of Teff cell–intrinsic Treg commitment programs. This was critical for stabilizing Teff cell functions and subverting immune-suppressive signals. T cell–specific deletion of Pcbp1 favored Treg cell differentiation, enlisted multiple inhibitory immune checkpoint molecules including PD-1, TIGIT, and VISTA on tumor-infiltrating lymphocytes, and blunted antitumor immunity. Our results demonstrate a critical role for PCBP1 as an intracellular immune checkpoint for maintaining Teff cell functions in cancer immunity.},

}

@article{aresuPhenotypicalCharacterizationClinical2021,

urldate = {2021-05-13},

abstract = {In dogs, Burkitt-like lymphoma (B-LL) is rare tumour and it is classified as a high-grade B-cell malignancy. The diagnosis is challenging because of the similar histologic appearance with other histotypes, no defined phenotypical criteria and poorly described clinical aspects. The aim of the study was to provide a detailed description of clinical and morphological features, as well as immunophenotypical profile of B-LL in comparison with the human counterpart. Thirteen dogs with histologically proven B-LL, for which a complete staging and follow-up were available, were retrospectively selected. Immunohistochemical expression of CD20, PAX5, CD3, CD10, BCL2, BCL6, MYC and caspase-3 was evaluated. Histologically, all B-LLs showed a diffuse architecture with medium to large-sized cells, high mitotic rate and diffuse starry sky appearance. B-phenotype of neoplastic cells was confirmed both by flow-cytometry and immunohistochemistry. Conversely, B-LLs were negative for BCL2 and MYC, whereas some cases co-expressed BCL6 and CD10, suggesting a germinal centre B-cell origin. Disease stage was advanced in the majority of cases. All dogs received CHOP-based chemotherapy with or without immunotherapy. Despite treatment, prognosis was poor, with a median time to progression and survival of 130 and 228 days, respectively. Nevertheless, approximately 30\% of dogs survived more than one year. An increased apoptotic index, a high turnover index and caspase-3 index correlated with shorter survival. In conclusion, canine B-LL shows phenotypical differences with the human counterpart along with features that might help to differentiate this entity from diffuse large B-cell lymphoma.},

langid = {english},

}

@article{arnedo-pacOncodriveCLUSTLSequencebasedClustering2019,

abstract = {MOTIVATION: Identification of the genomic alterations driving tumorigenesis is one of the main goals in oncogenomics research. Given the evolutionary principles of cancer development, computational methods that detect signals of positive selection in the pattern of tumor mutations have been effectively applied in the search for cancer genes. One of these signals is the abnormal clustering of mutations, which has been shown to be complementary to other signals in the detection of driver genes. RESULTS: We have developed OncodriveCLUSTL, a new sequence-based clustering algorithm to detect significant clustering signals across genomic regions. OncodriveCLUSTL is based on a local background model derived from the simulation of mutations accounting for the composition of tri- or penta-nucleotide context substitutions observed in the cohort under study. Our method can identify known clusters and bona-fide cancer drivers across cohorts of tumor whole-exomes, outperforming the existing OncodriveCLUST algorithm and complementing other methods based on different signals of positive selection. Our results indicate that OncodriveCLUSTL can be applied to the analysis of non-coding genomic elements and non-human mutations data. AVAILABILITY AND IMPLEMENTATION: OncodriveCLUSTL is available as an installable Python 3.5 package. The source code and running examples are freely available at https://bitbucket.org/bbglab/oncodriveclustl under GNU Affero General Public License. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.},

langid = {english},

pmcid = {PMC6853674},

}

@article{arthurGenomewideDiscoverySomatic2018,

abstract = {Diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer originating from mature B-cells. Prognosis is strongly associated with molecular subgroup, although the driver mutations that distinguish the two main subgroups remain poorly defined. Through an integrative analysis of whole genomes, exomes, and transcriptomes, we have uncovered genes and non-coding loci that are commonly mutated in DLBCL. Our analysis has identified novel cis-regulatory sites, and implicates recurrent mutations in the 3' UTR of NFKBIZ as a novel mechanism of oncogene deregulation and NF-κB pathway activation in the activated B-cell (ABC) subgroup. Small amplifications associated with over-expression of FCGR2B (the Fcγ receptor protein IIB), primarily in the germinal centre B-cell (GCB) subgroup, correlate with poor patient outcomes suggestive of a novel oncogene. These results expand the list of subgroup driver mutations that may facilitate implementation of improved diagnostic assays and could offer new avenues for the development of targeted therapeutics.},

langid = {english},

pmcid = {PMC6167379},

}

@article{ashrafuzzamanAptamersBothDrugs2014,

url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4177733/},

urldate = {2022-10-14},

abstract = {Aptamers are short nucleic acid oligos. They may serve as both drugs and drug-carriers. Their use as diagnostic tools is also evident. They can be generated using various experimental, theoretical, and computational techniques. The systematic evolution of ligands by exponential enrichment which uses iterative screening of nucleic acid libraries is a popular experimental technique. Theory inspired methodology entropy-based seed-and-grow strategy that designs aptamer templates to bind specifically to targets is another one. Aptamers are predicted to be highly useful in producing general drugs and theranostic drugs occasionally for certain diseases like cancer, Alzheimer's disease, and so on. They bind to various targets like lipids, nucleic acids, proteins, small organic compounds, and even entire organisms. Aptamers may also serve as drug-carriers or nanoparticles helping drugs to get released in specific target regions. Due to better target specific physical binding properties aptamers cause less off-target toxicity effects. Therefore, search for aptamer based drugs, drug-carriers, and even diagnostic tools is expanding fast. The biophysical properties in relation to the target specific binding phenomena of aptamers, energetics behind the aptamer transport of drugs, and the consequent biological implications will be discussed. This review will open up avenues leading to novel drug discovery and drug delivery.},

}

@article{assoulinePhaseStudyPanobinostat2016,

journaltitle = {Blood},

volume = {128},

number = {2},

}

@article{asterDetectionBCL2Rearrangements2002,

issn = {0002-9440},

url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1867166/},

urldate = {2023-12-18},

}

@article{auweraFastQDataHighConfidence2013,

urldate = {2019-12-21},

abstract = {This unit describes how to use BWA and the Genome Analysis Toolkit (GATK) to map genome sequencing data to a reference and produce high-quality variant calls that can be used in downstream analyses. The complete workflow includes the core NGS data-processing steps that are necessary to make the raw data suitable for analysis by the GATK, as well as the key methods involved in variant discovery using the GATK. Curr. Protoc. Bioinform. 43:11.10.1-11.10.33. © 2013 by John Wiley \& Sons, Inc.},

langid = {english},

}

@article{ayyadGeneExpressionCancer2019,

urldate = {2020-02-04},

abstract = {Gene expression microarray classification is a crucial research field as it has been employed in cancer prediction and diagnosis systems. Gene expression data are composed of dozens of samples characterized by thousands of genes. Hence, an accurate and effective classification of such samples is a challenge. Machine learning techniques have been broadly utilized to build substantial and precise classification models. This paper proposes a new classification technique for gene expression data, which is called Modified k-nearest neighbor (MKNN). MKNN is applied in two scenarios namely; smallest modified KNN (SMKNN) and largest modified KNN (LMKNN). Both implementations are undertaken to enhance the performance of KNN. The key idea is to employ robust neighbors from training data by using a new weighting strategy. Several experiments have been performed on six different gene expression datasets. Experiments have shown that MKNN in its both scenarios outperforms traditional as well as recent ones. MKNN has been compared against (i) KNN, (ii) weighted KNN, (iii) support vector machine (SVM), (iv) fuzzy support vector machine, (v) brain emotional learning (BEL) in terms of classification accuracy, precision, and recall. On the other hand, results show that MKNN introduces smaller testing time than both KNN and weighted KNN.},

langid = {english},

}

@article{balSuperenhancerHypermutationAlters2022,

abstract = {Diffuse large B~cell lymphoma (DLBCL) is the most common B cell non-Hodgkin lymphoma and remains incurable in around 40\% of patients. Efforts to sequence the coding genome identified several genes and pathways that are altered in this disease, including potential therapeutic targets1-5. However, the non-coding genome of DLBCL remains largely unexplored. Here we show that active super-enhancers are highly and specifically hypermutated in 92\% of samples from individuals with DLBCL, display signatures of activation-induced cytidine deaminase activity, and are linked to genes that encode B cell developmental regulators and oncogenes. As evidence of oncogenic relevance, we show that the hypermutated super-enhancers linked to the BCL6, BCL2 and CXCR4 proto-oncogenes prevent the binding and transcriptional downregulation of the corresponding target gene by transcriptional repressors, including BLIMP1 (targeting BCL6) and the steroid receptor NR3C1 (targeting BCL2 and CXCR4). Genetic correction of selected mutations restored repressor DNA binding, downregulated target gene expression and led to the counter-selection of cells containing corrected alleles, indicating an oncogenic dependency on the super-enhancer mutations. This pervasive super-enhancer mutational mechanism reveals a major set of genetic lesions deregulating gene expression, which expands the involvement of known oncogenes in DLBCL pathogenesis and identifies new deregulated gene targets of therapeutic relevance.},

langid = {english},

pmcid = {PMC9583699},

}

@article{baohuaMutationsPIK3CAGene,

journaltitle = {Diagnostic Molecular Pathology},

volume = {17},

number = {3},

}

@article{baoP53inducedLincRNAp21Derails2015,

abstract = {Recent studies have boosted our understanding of long noncoding RNAs (lncRNAs) in numerous biological processes, but few have examined their roles in somatic cell reprogramming. Through expression profiling and functional screening, we have identified that the large intergenic noncoding RNA p21 (lincRNA-p21) impairs reprogramming. Notably, lincRNA-p21 is induced by p53 but does not promote apoptosis or cell senescence in reprogramming. Instead, lincRNA-p21 associates with the H3K9 methyltransferase SETDB1 and the maintenance DNA methyltransferase DNMT1, which is facilitated by the RNA-binding protein HNRNPK. Consequently, lincRNA-p21 prevents reprogramming by sustaining H3K9me3 and/or CpG methylation at pluripotency gene promoters. Our results provide insight into the role of lncRNAs in reprogramming and establish a novel link between p53 and heterochromatin regulation.},

issue = {1},

langid = {english},

}

@article{barariaCathepsinAlterationsInduce2020c,

doi = {10.1016/j.celrep.2020.107522},

abstract = {Tumor cells orchestrate their microenvironment. Here, we provide biochemical, structural, functional, and clinical evidence that Cathepsin S (CTSS) alterations induce a tumor-promoting immune microenvironment in follicular lymphoma (FL). We found CTSS mutations at Y132 in 6\% of FL (19/305). Another 13\% (37/286) had CTSS amplification, which was associated with higher CTSS expression. CTSS Y132 mutations lead to accelerated autocatalytic conversion from an enzymatically inactive profrom to active CTSS and increased substrate cleavage, including CD74, which regulates major histocompatibility complex class II (MHC class II)-restricted antigen presentation. Lymphoma cells with hyperactive CTSS more efficiently activated antigen-specific CD4+ T~cells in~vitro. Tumors with hyperactive CTSS showed increased CD4+ T~cell infiltration and proinflammatory cytokine perturbation in a mouse model and in human FLs. In mice, this CTSS-induced immune microenvironment promoted tumor growth. Clinically, patients with CTSS-hyperactive FL had better treatment outcomes with standard immunochemotherapies, indicating that these immunosuppressive regimens target both the lymphoma cells and the tumor-promoting immune microenvironment.},

langid = {english},

}

@article{barnardPhaseClinicalTrial2014,

url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4203518/},

urldate = {2021-06-01},

abstract = {Autophagy is a lysosomal degradation process that may act as a mechanism of survival in a variety of cancers. While pharmacologic inhibition of autophagy with hydroxychloroquine (HCQ) is currently being explored in human clinical trials, it has never been evaluated in canine cancers. Non-Hodgkin lymphoma (NHL) is one of the most prevalent tumor types in dogs and has similar pathogenesis and response to treatment as human NHL. Clinical trials in canine patients are conducted in the same way as in human patients, thus, to determine a maximum dose of HCQ that can be combined with a standard chemotherapy, a Phase I, single arm, dose escalation trial was conducted in dogs with spontaneous NHL presenting as patients to an academic, tertiary-care veterinary teaching hospital. HCQ was administered daily by mouth throughout the trial, beginning 72 h prior to doxorubicin (DOX), which was given intravenously on a 21-d cycle. Peripheral blood mononuclear cells and biopsies were collected before and 3 d after HCQ treatment and assessed for autophagy inhibition and HCQ concentration. A total of 30 patients were enrolled in the trial. HCQ alone was well tolerated with only mild lethargy and gastrointestinal-related adverse events. The overall response rate (ORR) for dogs with lymphoma was 93.3\%, with median progression-free interval (PFI) of 5 mo. Pharmacokinetic analysis revealed a 100-fold increase in HCQ in tumors compared with plasma. There was a trend that supported therapy-induced increase in LC3-II (the cleaved and lipidated form of microtubule-associated protein 1 light chain 3/LC3, which serves as a maker for autophagosomes) and SQSTM1/p62 (sequestosome 1) after treatment. The superior ORR and comparable PFI to single-agent DOX provide strong support for further evaluation via randomized, placebo-controlled trials in canine and human NHL.},

}

@article{barrans1418Associated2003,

journaltitle = {Clin Cancer Res},

volume = {9},

number = {6},

}

@article{barthOfatumumabExhibitsEnhanced2015,

journaltitle = {Clin Cancer Res},

volume = {21},

number = {19},

}

@article{bassoBCL6MasterRegulator2010,

journaltitle = {Blood},

volume = {106},

number = {9},

}

@article{beaLandscapeSomaticMutations2013,

urldate = {2019-12-21},

abstract = {Mantle cell lymphoma (MCL) is an aggressive tumor, but a subset of patients may follow an indolent clinical course. To understand the mechanisms underlying this biological heterogeneity, we performed whole-genome and/or whole-exome sequencing on 29 MCL cases and their respective matched normal DNA, as well as 6 MCL cell lines. Recurrently mutated genes were investigated by targeted sequencing in an independent cohort of 172 MCL patients. We identified 25 significantly mutated genes, including known drivers such as ataxia-telangectasia mutated (ATM), cyclin D1 (CCND1), and the tumor suppressor TP53; mutated genes encoding the anti-apoptotic protein BIRC3 and Toll-like receptor 2 (TLR2); and the chromatin modifiers WHSC1, MLL2, and MEF2B. We also found NOTCH2 mutations as an alternative phenomenon to NOTCH1 mutations in aggressive tumors with a dismal prognosis. Analysis of two simultaneous or subsequent MCL samples by whole-genome/whole-exome (n = 8) or targeted (n = 19) sequencing revealed subclonal heterogeneity at diagnosis in samples from different topographic sites and modulation of the initial mutational profile at the progression of the disease. Some mutations were predominantly clonal or subclonal, indicating an early or late event in tumor evolution, respectively. Our study identifies molecular mechanisms contributing to MCL pathogenesis and offers potential targets for therapeutic intervention.},

langid = {english},

}

@article{behrensTranslationalSilencingFunction2018,

date = {2018-02},

journaltitle = {Nucleic Acids Res},

volume = {10},

}

@article{benesovaHansAlgorithmFailed,

journaltitle = {Neoplasma},

volume = {60},

number = {1},

}

@article{benhamouCMycMiR1792PTEN2018,

journaltitle = {Science translational medicine},

volume = {6},

number = {224},

}

@article{biffiElevatedLevelsGQuadruplex2014,

urldate = {2022-10-15},

abstract = {Four-stranded G-quadruplex DNA secondary structures have recently been visualized in the nuclei of human cultured cells. Here, we show that BG4, a G-quadruplex-specific antibody, can be used to stain DNA G-quadruplex structures in patient-derived tissues using immunohistochemistry. We observe a significantly elevated number of G-quadruplex-positive nuclei in human cancers of the liver and stomach as compared to background non-neoplastic tissue. Our results suggest that G-quadruplex formation can be detected and measured in patient-derived material and that elevated G-quadruplex formation may be a characteristic of some cancers.},

langid = {english},

}

@article{blenkGerminalCenterCelllike2007,

date = {2007},

journaltitle = {Cancer informatics},

volume = {3},

}

@article{blumSnapShotTCGAAnalyzedTumors2018,

doi = {10.1016/j.cell.2018.03.059},

url = {https://www.cell.com/cell/abstract/S0092-8674(18)30391-X},

urldate = {2022-05-23},

}

@article{boevaControlFREECToolAssessing2012,

url = {https://academic.oup.com/bioinformatics/article/28/3/423/189142},

urldate = {2019-07-08},

abstract = {Abstract. Summary: More and more cancer studies use next-generation sequencing (NGS) data to detect various types of genomic variation. However, even when rese},

}

@article{bohersTargetableActivatingMutations,

journaltitle = {Genes Chromosome Canc},

volume = {53},

number = {2},

}

@article{bohleRoleEarlyBcell2013,

journaltitle = {Expert opinion on pharmacotherapy},

volume = {15},

number = {16},

}

@article{bothamSmallMoleculeProcaspase3Activation2016,

doi = {10.1021/acscentsci.6b00165},

abstract = {Conventional chemotherapeutics remain essential treatments for most cancers, but their combination with other anticancer drugs (including targeted therapeutics) is often complicated by unpredictable synergies and multiplicative toxicities. As cytotoxic anticancer chemotherapeutics generally function through induction of apoptosis, we hypothesized that a molecularly targeted small molecule capable of facilitating a central and defining step in the apoptotic cascade, the activation of procaspase-3 to caspase-3, would broadly and predictably enhance activity of cytotoxic drugs. Here we show that procaspase-activating compound 1 (PAC-1) enhances cancer cell death induced by 15 different FDA-approved chemotherapeutics, across many cancer types and chemotherapeutic targets. In particular, the promising combination of PAC-1 and doxorubicin induces a synergistic reduction in tumor burden and enhances survival in murine tumor models of osteosarcoma and lymphoma. This PAC-1/doxorubicin combination was evaluated in 10 pet dogs with naturally occurring metastatic osteosarcoma or lymphoma, eliciting a biologic response in 3 of 6 osteosarcoma patients and 4 of 4 lymphoma patients. Importantly, in both mice and dogs, coadministration of PAC-1 with doxorubicin resulted in no additional toxicity. On the basis of the mode of action of PAC-1 and the high expression of procaspase-3 in many cancers, these results suggest the combination of PAC-1 with cytotoxic anticancer drugs as a potent and general strategy to enhance therapeutic response.},

langid = {english},

}

@article{boutrosGlobalOptimizationSomatic2014,

doi = {10.1038/ng.2932},

langid = {english},

pmcid = {PMC4035501},

}

@article{boutrosGlobalOptimizationSomatic2014a,

doi = {10.1038/ng.2932},

langid = {english},

pmcid = {PMC4035501},

}

@article{bowlerMisidentificationMLL3Other2019,

journaltitle = {Immunology and cell biology},

volume = {91},

number = {5},

}

@article{braggioGenomicAnalysisMarginal2012,

abstract = {Lymphoplasmacytic lymphomas and marginal zone lymphomas of nodal, extra-nodal and splenic types account for 10\% of non-Hodgkin lymphomas. They are similar at the cell differentiation level, sometimes making difficult to distinguish them from other indolent non-Hodgkin lymphomas. To better characterize their genetic basis, we performed array-based comparative genomic hybridization in 101 marginal zone lymphomas (46 MALT, 35 splenic and 20 nodal marginal zone lymphomas) and 13 lymphoplasmacytic lymphomas. Overall, 90\% exhibited copy-number abnormalities. Lymphoplasmacytic lymphomas demonstrated the most complex karyotype (median=7 copy-number abnormalities), followed by MALT (4), nodal (3.5) and splenic marginal zone lymphomas (3). A comparative analysis exposed a group of copy-number abnormalities shared by several or all the entities with few disease-specific abnormalities. Gain of chromosomes 3, 12 and 18 and loss of 6q23-q24 (TNFAIP3) were identified in all entities. Losses of 13q14.3 (MIRN15A-MIRN16-1) and 17p13.3-p12 (TP53) were found in lymphoplasmacytic and splenic marginal zone lymphomas; loss of 11q21-q22 (ATM) was found in nodal, splenic marginal zone and lymphoplasmacytic lymphomas and loss of 7q32.1-q33 was found in MALT, splenic and lymphoplasmacytic lymphomas. Abnormalities affecting the nuclear factor kappa B pathway were observed in 70\% of MALT and lymphoplasmacytic lymphomas and 30\% of splenic and nodal marginal zone lymphomas, suggesting distinct roles of this pathway in the pathogenesis/progression of these subtypes. Elucidation of the genetic alterations contributing to the pathogenesis of these lymphomas may guide to design-specific therapeutic approaches.},

langid = {english},

pmcid = {PMC3341516},

}

@article{brazmaMinimumInformationMicroarray2001,

doi = {10.1038/ng1201-365},

abstract = {Microarray analysis has become a widely used tool for the generation of gene expression data on a genomic scale. Although many significant results have been derived from microarray studies, one limitation has been the lack of standards for presenting and exchanging such data. Here we present a proposal, the Minimum Information About a Microarray Experiment (MIAME), that describes the minimum information required to ensure that microarray data can be easily interpreted and that results derived from its analysis can be independently verified. The ultimate goal of this work is to establish a standard for recording and reporting microarray-based gene expression data, which will in turn facilitate the establishment of databases and public repositories and enable the development of data analysis tools. With respect to MIAME, we concentrate on defining the content and structure of the necessary information rather than the technical format for capturing it.},

langid = {english},

}

@article{brazmaMINSEQEMinimumInformation2012,

urldate = {2022-05-19},

abstract = {MINSEQE~describes the~Minimum Information about a high-throughput nucleotide SEQuencing Experiment~that is needed to enable the unambiguous interpretation and facilitate reproduction of the results of the~experiment. By analogy to the~MIAME~guidelines for microarray experiments, adherence to the MINSEQE guidelines will improve~integration of multiple experiments across different modalities, thereby maximising the value of high-throughput research.~ The five elements of experimental description considered essential when making data available supporting published high-throughput sequencing experiments are as follows: The description of the biological system, samples, and the experimental variables being studied: “compound” and “dose” in dose-response experiments or “antibody” in ChIP-Seq experiments,~the organism, tissue, and the ~treatment(s) applied. The sequence read data for each assay: read sequences and base-level quality scores for each assay;~FASTQ~format is recommended, with a description of the scale used for quality scores. The ‘final’ processed (or summary) data for the set of assays in the study: the data on which the conclusions in the related publication are based, and~descriptions of the data format. General information about the experiment and sample-data relationships: a summary of the experiment and its goals, contact information, any associated publication, and a~table specifying sample-data relationships. Essential experimental and data processing protocols: how the nucleic acid samples were isolated, purified and processed prior to sequencing,~a summary of the instrumentation used, library preparation strategy, labelling and amplification methodologies, alignment algorithms and data filtering plus data processing \& analysis protocols. The present document contains version 1.0 of the MINSEQE guidelines, which~originated from discussions at an FGED-organized workshop held in Berkeley in March 2008.},

langid = {english},

}

@article{breenEvolutionarilyConservedCytogenetic2008,

url = {https://doi.org/10.1007/s10577-007-1212-4},

urldate = {2021-05-28},

abstract = {The pathophysiological similarities shared by many forms of human and canine disease, combined with the sophisticated genomic resources now available for the dog, have placed ‘man’s best friend’ in a position of high visibility as a model system for a variety of biomedical concerns, including cancer. The importance of nonrandom cytogenetic abnormalities in human leukemia and lymphoma was recognized over 40~years ago, but the mechanisms of genome reorganization remain incompletely understood. The development of molecular cytogenetics, using fluorescence in situ hybridization (FISH) technology, has played a significant role in our understanding of cancer biology by providing a means for ‘interrogating’ tumor cells for a variety of gross genetic changes in the form of either numerical or structural chromosome aberrations. Here, we have identified cytogenetic abnormalities in naturally occurring canine hematopoietic tumors that are evolutionarily conserved compared with those that are considered characteristic of the corresponding human condition. These data suggest that humans and dogs share an ancestrally retained pathogenetic basis for cancer and that cytogenetic evaluation of canine tumors may provide greater insight into the biology of tumorigenesis.},

}

@article{bresciaMEF2BInstructsGerminal2018,

url = {https://www.cell.com/cancer-cell/abstract/S1535-6108(18)30366-0},

urldate = {2019-12-21},

langid = {english},

}

@article{breunisCopyNumberVariation2009,

journaltitle = {Human mutation},

volume = {30},

number = {5},

}

@article{brooksPanCancerAnalysisTranscriptome2014,

urldate = {2020-09-22},

abstract = {Although recurrent somatic mutations in the splicing factor U2AF1 (also known as U2AF35) have been identified in multiple cancer types, the effects of these mutations on the cancer transcriptome have yet to be fully elucidated. Here, we identified splicing alterations associated with U2AF1 mutations across distinct cancers using DNA and RNA sequencing data from The Cancer Genome Atlas (TCGA). Using RNA-Seq data from 182 lung adenocarcinomas and 167 acute myeloid leukemias (AML), in which U2AF1 is somatically mutated in 3–4\% of cases, we identified 131 and 369 splicing alterations, respectively, that were significantly associated with U2AF1 mutation. Of these, 30 splicing alterations were statistically significant in both lung adenocarcinoma and AML, including three genes in the Cancer Gene Census, CTNNB1, CHCHD7, and PICALM. Cell line experiments expressing U2AF1 S34F in HeLa cells and in 293T cells provide further support that these altered splicing events are caused by U2AF1 mutation. Consistent with the function of U2AF1 in 3′ splice site recognition, we found that S34F/Y mutations cause preferences for CAG over UAG 3′ splice site sequences. This report demonstrates consistent effects of U2AF1 mutation on splicing in distinct cancer cell types.},

langid = {english},

}

@article{bruunGlobalIdentificationHnRNP2016,

url = {https://doi.org/10.1186/s12915-016-0279-9},

urldate = {2022-10-14},

abstract = {Many pathogenic genetic variants have been shown to disrupt mRNA splicing. Besides splice mutations in the well-conserved splice sites, mutations in splicing regulatory elements (SREs) may deregulate splicing and cause disease. A promising therapeutic approach is to compensate for this deregulation by blocking other SREs with splice-switching oligonucleotides (SSOs). However, the location and sequence of most SREs are not well known.},

}

@article{buntingNewEffectorFunctions2013,

url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4075446/},

urldate = {2022-10-06},

abstract = {The BCL6 oncogenic repressor is a master regulator of humoral immunity and B-cell lymphoma survival. Whereas much research has focused on its regulation and function in germinal center B-cells, its role in other mature lymphoid cell compartments is less clear. A novel role for BCL6 in follicular T helper cell development was recently uncovered. The latest discoveries reveal that BCL6 is also an important regulator of other specialized helper T-cell subsets within germinal centers, pre-germinal center events, and peripheral T-cells effector functions. Here, we review newly discovered roles for BCL6 in lymphocyte subsets residing within and outside of germinal centers, and discuss their implications with respect to the molecular mechanisms of BCL6 regulation and potential links to B and T-cell lymphomas.},

}

@article{burkhardtClinicalRelevanceMolecular2022b,

abstract = {While survival has improved for Burkitt lymphoma patients, potential differences in outcome between pediatric and adult patients remain unclear. In both age groups, survival remains poor at relapse. Therefore, we conducted a comparative study in a large pediatric cohort, including 191 cases and 97 samples from adults. While TP53 and CCND3 mutation frequencies are not age related, samples from pediatric patients showed a higher frequency of mutations in ID3, DDX3X, ARID1A and SMARCA4, while several genes such as BCL2 and YY1AP1 are almost exclusively mutated in adult patients. An unbiased analysis reveals a transition of the mutational profile between 25 and 40 years of age. Survival analysis in the pediatric cohort confirms that TP53 mutations are significantly associated with higher incidence of relapse (25\,±\,4\% versus 6\,±\,2\%, p-value 0.0002). This identifies a promising molecular marker for relapse incidence in pediatric BL which will be used in future clinical trials.},

langid = {english},

pmcid = {PMC9259584},

}

@article{burrowsCellDevelopmentDifferentiation1997,

url = {https://www.sciencedirect.com/science/article/pii/S0952791597801422},

urldate = {2022-10-06},

abstract = {The initial phases of B cell development depend on interactions between the cell surface molecules and secreted products of stromal cells with their receptor-ligand partners on lymphoid progenitors. Recent research in this area has greatly advanced our understanding of B cell development and differentiation. Antigen receptors on pre-B and B cells play key roles in the progression of this differentiation process, as revealed by targeted and inherited gene mutations that disrupt B cell development and by the transgenic repair of these mutations in mice.},

}

@article{burtonNCIComparativeOncology2018,

url = {https://clincancerres.aacrjournals.org/content/24/23/5830},

urldate = {2022-01-11},

abstract = {Purpose: Only one chemical class of topoisomerase I (TOP1) inhibitors is FDA approved, the camptothecins with irinotecan and topotecan widely used. Because of their limitations (chemical instability, drug efflux-mediated resistance, and diarrhea), novel TOP1 inhibitors are warranted. Indenoisoquinoline non-camptothecin topoisomerase I (TOP1) inhibitors overcome chemical instability and drug resistance that limit camptothecin use. Three indenoisoquinolines, LMP400 (indotecan), LMP776 (indimitecan), and LMP744, were examined in a phase I study for lymphoma-bearing dogs to evaluate differential efficacy, pharmacodynamics, toxicology, and pharmacokinetics. Experimental Design: Eighty-four client-owned dogs with lymphomas were enrolled in dose-escalation cohorts for each indenoisoquinoline, with an expansion phase for LMP744. Efficacy, tolerability, pharmacokinetics, and target engagement were determined. Results: The MTDs were 17.5 mg/m2 for LMP 776 and 100 mg/m2 for LMP744; bone marrow toxicity was dose-limiting; up to 65 mg/m2 LMP400 was well-tolerated and MTD was not reached. None of the drugs induced notable diarrhea. Sustained tumor accumulation was observed for LMP744; γH2AX induction was demonstrated in tumors 2 and 6 hours after treatment; a decrease in TOP1 protein was observed in most lymphoma samples across all compounds and dose levels, which is consistent with the fact that tumor response was also observed at low doses LMP744. Objective responses were documented for all indenoisoquinolines; efficacy (13/19 dogs) was greatest for LMP744. Conclusions: These results demonstrate proof-of-mechanism for indenoisoquinoline TOP1 inhibitors supporting their further clinical development. They also highlight the value of the NCI Comparative Oncology Program (https://ccr.cancer.gov/Comparative-Oncology-Program) for evaluating novel therapies in immunocompetent pets with cancers.},

}

@article{bushellGeneticInactivationTRAF32015,

doi = {10.1182/blood-2014-10-602714},

abstract = {Non-Hodgkin lymphomas (NHLs) are the most common cancer to affect pet dogs. In contrast to the many genes whose mutation contributes to lymphomagenesis in humans, relatively little is known about the acquired genetic alterations that lead to canine B-cell lymphomas (cBCLs). We performed a survey of 84 canine NHL tumors to identify genes affected by somatic point mutations. We found mutations affecting TRAF3, which encodes a negative regulator of nuclear factor (NF)-κB, to be a common feature of cBCLs, with mutations observed in 44\% of tumors including a combination of somatic and rare germ-line variants. Overall, 30\% of the tumors contained ≥1 somatic TRAF3 mutation. The majority of mutations are predicted to cause loss of TRAF3 protein including those impacting reading frame and splicing. To determine whether TRAF3 loss might be relevant to human NHL, we also analyzed 148 human diffuse large B-cell lymphoma (DLBCL) tumors and identified loss of TRAF3 as a common event, affecting ∼9\% of DLBCLs, and reduced expression of TRAF3 among deleted cases. This study implicates mutations affecting NF-κB activity as a novel genetic commonality between human and canine NHLs and supports the potential utility of cBCLs with mutated TRAF3 as a model of the more aggressive activated B-cell subgroup of DLBCL.},

langid = {english},

}

@article{bustinMIQEGuidelinesMinimum2009,

doi = {10.1373/clinchem.2008.112797},

url = {https://doi.org/10.1373/clinchem.2008.112797},

urldate = {2022-05-19},

}

@article{butcharReciprocalRegulationActivating2010,

journaltitle = {Clin Cancer Res},

volume = {16},

number = {7},

}

@article{callananIgGFcReceptor2000,

issn = {0027-8424},

doi = {10.1073/pnas.97.1.309},

url = {http://dx.doi.org/10.1073/pnas.97.1.309},

}

@article{camilleri-broetFcgammaRIIBDifferentiallyExpressed2004,

journaltitle = {Br J Haematol},

volume = {124},

number = {1},

}

@article{campoInternationalConsensusClassification2022,

abstract = {Since the publication of the Revised European-American Classification of Lymphoid Neoplasms in 1994, subsequent updates of the classification of lymphoid neoplasms have been generated through iterative international efforts to achieve broad consensus among hematopathologists, geneticists, molecular scientists, and clinicians. Significant progress has recently been made in the characterization of malignancies of the immune system, with many new insights provided by genomic studies. They have led to this proposal. We have followed the same process that was successfully used for the third and fourth editions of the World Health Organization Classification of Hematologic Neoplasms. The definition, recommended studies, and criteria for the diagnosis of many entities have been extensively refined. Some categories considered provisional have now been upgraded to definite entities. Terminology for some diseases has been revised to adapt nomenclature to the current knowledge of their biology, but these modifications have been restricted to well-justified situations. Major findings from recent genomic studies have impacted the conceptual framework and diagnostic criteria for many disease entities. These changes will have an impact on optimal clinical management. The conclusions of this work are summarized in this report as the proposed International Consensus Classification of mature lymphoid, histiocytic, and dendritic cell tumors.},

langid = {english},

pmcid = {PMC9479027},

}

@article{cannellPleiotropicRNABindingProtein2015,

url = {https://www.cambridge.org/core/journals/american-antiquity/article/early-storage-and-sedentism-on-the-pacific-northwest-coast-ancient-dna-analysis-of-salmon-remains-from-namu-british-columbia/55BF5175B9F47DCB521786EF5F8EF3BC},

urldate = {2018-10-27},

abstract = {Ancient DNA identification of salmon remains from the site of Namu on the central coast of British Columbia shows use of a variety of species and an emphasis on pink salmon over the course of the past 7,000 years. These results support arguments that Namu was a permanent village settlement dependent on a salmon storage economy throughout this time. This pattern of subsistence and settlement predates by several millennia the first substantial evidence for population expansion or social differentiation in the region. Periodic salmon shortages in the period after 2000 cal B.C., which are associated with local and regional disruptions in settlement and increased reliance on more marginal resources, appear to be the result of failures in the pink salmon fishery. , Résumé La identificación del ADN antiguo en remanentes de salmón obtenidos en el sitio Namu en la costa central de la Columbia Británica, constituye evidencia de la utilización de una variedad de especies, con preferencia por el salmón rosado, a través de los últimos 7000 años. Dichos resultados vendrían a apoyar la hipótesis de que Namu sería un asentamiento permanente, que dependería económicamente del almacenamiento de salmón. Este patrón de subsistencia y de asentamiento vendría a ser más temprano, por varios milenios, que la importante primera evidencia de una expansión poblacional o de una diferenciación social en esta región. La escasez periódica del salmón en el período posterior al 2000 cal B.C., asociada con trastornos en los asentamientos locales y regionales y con un incremento de la dependencia sobre recursos más marginales, vendrían a ser producto del fracaso en la pesca del salmón rosado.},

}

@article{caoControlAlternativeSplicing2012,

url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3439897/},

urldate = {2022-09-22},

abstract = {The molecular basis of cell signal-regulated alternative splicing at the 3′ splice site remains largely unknown. We isolated a protein kinase A-responsive ribonucleic acid (RNA) element from a 3′ splice site of the synaptosomal-associated protein 25 (Snap25) gene for forskolin-inhibited splicing during neuronal differentiation of rat pheochromocytoma PC12 cells. The element binds specifically to heterogeneous nuclear ribonucleo protein (hnRNP) K in a phosphatase-sensitive way, which directly competes with the U2 auxiliary factor U2AF65, an essential component of early spliceosomes. Transcripts with similarly localized hnRNP K target motifs upstream of alternative exons are enriched in genes often associated with neurological diseases. We show that such motifs upstream of the Runx1 exon 6 also bind hnRNP K, and importantly, hnRNP K is required for forskolin-induced repression of the exon. Interestingly, this exon encodes the peptide domain that determines the switch of the transcriptional repressor/activator activity of Runx1, a change known to be critical in specifying neuron lineages. Consistent with an important role of the target genes in neurons, knocking down hnRNP K severely disrupts forskolin-induced neurite growth. Thus, through hnRNP K, the neuronal differentiation stimulus forskolin targets a critical 3′ splice site component of the splicing machinery to control alternative splicing of crucial genes. This also provides a regulated direct competitor of U2AF65 for cell signal control of 3′ splice site usage.},

}

@article{caputiDeterminationRNABinding2001,

url = {https://www.jbc.org/article/S0021-9258(19)82817-X/abstract},

urldate = {2022-09-26},

abstract = {{$<$}p{$>$}Members of the heterogeneous nuclear ribonucleoprotein (hnRNP) H protein family, H, H′, F, and 2H9, are involved in pre-mRNA processing. We analyzed the assembly of these proteins from splicing extracts onto four RNA regulatory elements as follows: a high affinity hnRNP A1-binding site (WA1), a sequence involved in Rev-dependent export (p17gag INS), an exonic splicing silencer from the β-tropomyosin gene, and an intronic splicing regulator (downstream control sequence (DCS) from the c-\emph{src} gene. The entire family binds the WA1, instability (INS), and β-tropomyosin substrates, and the core-binding site for each is a run of three G residues followed by an A. Transfer of small regions containing this sequence to a substrate lacking hnRNP H binding activity is sufficient to promote binding of all family members. The c-\emph{src} DCS has been shown to assemble hnRNP H, not hnRNP F, from HeLa cell extracts, and we show that hnRNP 2H9 does not bind this element. The DCS contains five G residues followed by a C. Mutation of the C to an A changes the specificity of the DCS from a substrate that binds only hnRNP H/H′ to a binding site for all hnRNP H family members. We conclude that the sequence GGGA is recognized by all hnRNP H family proteins.{$<$}/p{$>$}},

}

@article{carabetComputerAidedDiscoverySmall2019,

abstract = {The heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) is a versatile RNA-binding protein playing a critical role in alternative pre-mRNA splicing regulation in cancer. Emerging data have implicated hnRNP A1 as a central player in a splicing regulatory circuit involving its direct transcriptional control by c-Myc oncoprotein and the production of the constitutively active ligand-independent alternative splice variant of androgen receptor, AR-V7, which promotes castration-resistant prostate cancer (CRPC). As there is an urgent need for effective CRPC drugs, targeting hnRNP A1 could, therefore, serve a dual purpose of preventing AR-V7 generation as well as reducing c-Myc transcriptional output. Herein, we report compound VPC-80051 as the first small molecule inhibitor of hnRNP A1 splicing activity discovered to date by using a computer-aided drug discovery approach. The inhibitor was developed to target the RNA-binding domain (RBD) of hnRNP A1. Further experimental evaluation demonstrated that VPC-80051 interacts directly with hnRNP A1 RBD and reduces AR-V7 messenger levels in 22Rv1 CRPC cell line. This study lays the groundwork for future structure-based development of more potent and selective small molecule inhibitors of hnRNP A1⁻RNA interactions aimed at altering the production of cancer-specific alternative splice isoforms.},

langid = {english},

pmcid = {PMC6413181},

}

@article{carlottiTransformationFollicularLymphoma,

journaltitle = {Blood},

volume = {113},

number = {15},

}

@article{carnetrecessonBCLXLDirectlyModulates2017,

url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5654832/},

urldate = {2022-10-04},

abstract = {In tumours, accumulation of chemoresistant cells that express high levels of anti-apoptotic proteins such as BCL-XL is thought to result from the counter selection of sensitive, low expresser clones during progression and/or initial treatment. We herein show that BCL-XL expression is selectively advantageous to cancer cell populations even in the absence of pro-apoptotic pressure. In transformed human mammary epithelial cells BCL-XL favours full activation of signalling downstream of constitutively active RAS with which it interacts in a BH4-dependent manner. Comparative proteomic analysis and functional assays indicate that this is critical for RAS-induced expression of stemness regulators and maintenance of a cancer initiating cell (CIC) phenotype. Resistant cancer cells thus arise from a positive selection driven by BCL-XL modulation of RAS-induced self-renewal, and during which apoptotic resistance is not necessarily the directly selected trait., BCL-XL provides a survival advantage to cancer cells even in the absence of apoptotic pressures. In this study, the authors show that BCL-XL interacts with RAS in a BH4-dependent manner and regulates RAS-mediated activation of pathways involved in the stemness feature of breast cancer cells.},

}

@article{carpenterHeterogeneousNuclearRibonucleoprotein2006,

abstract = {Heterogeneous ribonucleoprotein K (hnRNP K) is a member of the hnRNP family which has several different cellular roles including transcription, mRNA shuttling, RNA editing and translation. Several reports implicate hnRNP K having a role in tumorigenesis, for instance hnRNP K increases transcription of the oncogene c-myc and hnRNP K expression is regulated by the p53/MDM 2 pathway. In this study comparing normal colon to colorectal cancer by proteomics, hnRNP K was identified as being overexpressed in this type of cancer. Immunohistochemistry with a monoclonal antibody to hnRNP K (which we developed) on colorectal cancer tissue microarray, confirmed that hnRNP K was overexpressed in colorectal cancer (P{$<$}0.001) and also showed that hnRNP K had an aberrant subcellular localisation in cancer cells. In normal colon hnRNP K was exclusively nuclear whereas in colorectal cancer the protein localised both in the cytoplasm and the nucleus. There were significant increases in both nuclear (P=0.007) and cytoplasmic (P=0.001) expression of hnRNP K in Dukes C tumours compared with early stage tumours. In Dukes C patient's good survival was associated with increased hnRNP K nuclear expression (P=0.0093). To elaborate on the recent observation that hnRNP K is regulated by p53, the expression profiles of these two proteins were also analysed. There was no correlation between hnRNP K and p53 expression, however, patients who presented tumours that were positive for hnRNP K and p53 had a poorer survival outcome (P=0.045).},

issue = {7},

langid = {english},

}

@article{castelo-brancoPolypyrimidineTractBinding2004,

publisher = {American Society for Microbiology},

doi = {10.1128/MCB.24.10.4174-4183.2004},

url = {https://journals.asm.org/doi/full/10.1128/MCB.24.10.4174-4183.2004},

}

@article{cattorettiDeregulatedBCL6Expression,

journaltitle = {Cancer Cell},

volume = {7},

number = {5},

}

@article{cattorettiTargetedDisruptionS1P22009,

journaltitle = {Cancer Res},

volume = {69},

number = {22},

}

@online{CellDevelopmentPathways,

url = {https://www.proquest.com/openview/dd4dd441a1e721485aa871b6e812c2d9/1?casa_token=oL4JXwb4PmAAAAAA:a05XBzPaGKSPDIrAWvwnlVXDB-bn8l3cKX0AQ5lllmjo9zPxpqzckoiCzUkPoAs0C7TDTeBPQuw&cbl=47332&pq-origsite=gscholar&parentSessionId=vkSsFp6eiGXrMO9pT3aWhVFysFqfdTwKAN1ymj7w48c%3D},

urldate = {2022-10-06},

abstract = {Explore millions of resources from scholarly journals, books, newspapers, videos and more, on the ProQuest Platform.},

}

@article{cerchiettiPurineScaffoldHsp902009,

abstract = {By taking advantage of the direct interaction between heat shock protein 90 (Hsp90) and the transcriptional repressor Bcl-6, a purine-derived inhibitor of Hsp90 selectively kills diffuse large B cell lymphomas that depend on the expression of Bcl-6 for their survival.},

issue = {12},

langid = {english},

}

@article{chadburnImmunophenotypicAnalysisAIDSrelated,

journaltitle = {J Clin Oncol},

volume = {27},

number = {30},

}

@article{changRNAbindingProteinHnRNPLL2015,

publisher = {Proceedings of the National Academy of Sciences},

doi = {10.1073/pnas.1422490112},

url = {https://www.pnas.org/doi/10.1073/pnas.1422490112},

}

@article{changTargetingPanessentialGenes2021,

urldate = {2023-01-09},

abstract = {Despite remarkable successes in the clinic, cancer targeted therapy development remains challenging and the failure rate is disappointingly high. This problem is partly due to the misapplication of the targeted therapy paradigm to therapeutics targeting pan-essential genes, which can result in therapeutics whereby efficacy is attenuated by dose-limiting toxicity. Here we summarize the key features of successful chemotherapy and targeted therapy agents, and use case studies to outline recurrent challenges to drug development efforts targeting pan-essential genes. Finally, we suggest strategies to avoid previous pitfalls for ongoing and future development of pan-essential therapeutics.},

langid = {english},

}

@article{chanPathogenesisDiffuseLarge2010,

journaltitle = {International journal of hematology},

volume = {92},

number = {2},

}

@article{chapuyDiscoveryCharacterizationSuperEnhancerAssociated2013,

journaltitle = {Cancer Cell},

volume = {24},

number = {6},

}

@article{chapuyGenomicAnalysesPMBL2019b,

abstract = {Primary mediastinal large B-cell lymphomas (PMBLs) are aggressive tumors that typically present as large mediastinal masses in young women. PMBLs share clinical, transcriptional, and molecular features with classical Hodgkin lymphoma (cHL), including constitutive activation of nuclear factor κB (NF-κB), JAK/STAT signaling, and programmed cell death protein 1 (PD-1)-mediated immune evasion. The demonstrated efficacy of PD-1 blockade in relapsed/refractory PMBLs led to recent approval by the US Food and Drug Administration and underscored the importance of characterizing targetable genetic vulnerabilities in this disease. Here, we report a comprehensive analysis of recurrent genetic alterations -somatic mutations, somatic copy number alterations, and structural variants-in a cohort of 37 newly diagnosed PMBLs. We identified a median of 9 genetic drivers per PMBL, including known and newly identified components of the JAK/STAT and NF-κB signaling pathways and frequent B2M alterations that limit major histocompatibility complex class I expression, as in cHL. PMBL also exhibited frequent, newly identified driver mutations in ZNF217 and an additional epigenetic modifier, EZH2. The majority of these alterations were clonal, which supports their role as early drivers. In PMBL, we identified several previously uncharacterized molecular features that may increase sensitivity to PD-1 blockade, including high tumor mutational burden, microsatellite instability, and an apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) mutational signature. The shared genetic features between PMBL and cHL provide a framework for analyzing the mechanism of action of PD-1 blockade in these related lymphoid malignancies.},

langid = {english},

pmcid = {PMC6933293},

}

@article{chapuyMolecularSubtypesDiffuse2018b,

abstract = {Diffuse large B cell lymphoma (DLBCL), the most common lymphoid malignancy in adults, is a clinically and genetically heterogeneous disease that is further classified into transcriptionally defined activated B cell (ABC) and germinal center B cell (GCB) subtypes. We carried out a comprehensive genetic analysis of 304 primary DLBCLs and identified low-frequency alterations, captured recurrent mutations, somatic copy number alterations, and structural variants, and defined coordinate signatures in patients with available outcome data. We integrated these genetic drivers using consensus clustering and identified five robust DLBCL subsets, including a previously unrecognized group of low-risk ABC-DLBCLs of extrafollicular/marginal zone origin; two distinct subsets of GCB-DLBCLs with different outcomes and targetable alterations; and an ABC/GCB-independent group with biallelic inactivation of TP53, CDKN2A loss, and associated genomic instability. The genetic features of the newly characterized subsets, their mutational signatures, and the temporal ordering of identified alterations provide new insights into DLBCL pathogenesis. The coordinate genetic signatures also predict outcome independent of the clinical International Prognostic Index and suggest new combination treatment strategies. More broadly, our results provide a roadmap for an actionable DLBCL classification.},

langid = {english},

pmcid = {PMC6613387},

}

@article{chaudhuryHeterogeneousNuclearRibonucleoproteins2010,

url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2905745/},

urldate = {2022-09-28},

abstract = {Heterogeneous nuclear ribonucleoproteins (hnRNPs) comprise a family of RNA-binding proteins. The complexity and diversity associated with the hnRNPs render them multifunctional, involved not only in processing heterogeneous nuclear RNAs (hnRNAs) into mature mRNAs, but also acting as trans-factors in regulating gene expression. Heterogeneous nuclear ribonucleoprotein E1 (hnRNP E1), a subgroup of hnRNPs, is a KH-triple repeat containing RNA-binding protein. It is encoded by an intronless gene arising from hnRNP E2 through a retrotransposition event. hnRNP E1 is ubiquitously expressed and functions in regulating major steps of gene expression, including pre-mRNA processing, mRNA stability, and translation. Given its wide-ranging functions in the nucleus and cytoplasm and interaction with multiple proteins, we propose a post-transcriptional regulon model that explains hnRNP E1's widespread functional diversity.},

}

@article{chaudhuryTGFbetamediatedPhosphorylationHnRNP2010,

abstract = {Transforming growth factor-beta (TGF-beta) induces epithelial-mesenchymal transdifferentiation (EMT) accompanied by cellular differentiation and migration. Despite extensive transcriptomic profiling, the identification of TGF-beta-inducible, EMT-specific genes has met with limited success. Here we identify a post-transcriptional pathway by which TGF-beta modulates the expression of EMT-specific proteins and of EMT itself. We show that heterogeneous nuclear ribonucleoprotein E1 (hnRNP E1) binds a structural, 33-nucleotide TGF-beta-activated translation (BAT) element in the 3' untranslated region of disabled-2 (Dab2) and interleukin-like EMT inducer (ILEI) transcripts, and represses their translation. TGF-beta activation leads to phosphorylation at Ser 43 of hnRNP E1 by protein kinase Bbeta/Akt2, inducing its release from the BAT element and translational activation of Dab2 and ILEI messenger RNAs. Modulation of hnRNP E1 expression or its post-translational modification alters the TGF-beta-mediated reversal of translational silencing of the target transcripts and EMT. These results suggest the existence of a TGF-beta-inducible post-transcriptional regulon that controls EMT during the development and metastatic progression of tumours.},

langid = {english},

pmcid = {PMC2830561},

}

@article{cheahMantleCellLymphoma2016,

abstract = {Oxford Nanopore sequencing can be used to achieve complete bacterial genomes. However, the error rates of Oxford Nanopore long reads are greater compared to Illumina short reads. Long-read assemblers using a variety of assembly algorithms have been developed to overcome this deficiency, which have not been benchmarked for genomic analyses of bacterial pathogens using Oxford Nanopore long reads. In this study, long-read assemblers, namely Canu, Flye, Miniasm/Racon, Raven, Redbean, and Shasta, were thus benchmarked using Oxford Nanopore long reads of bacterial pathogens. Ten species were tested for mediocre- and low-quality simulated reads, and 10 species were tested for real reads. Raven was the most robust assembler, obtaining complete and accurate genomes. All Miniasm/Racon and Raven assemblies of mediocre-quality reads provided accurate antimicrobial resistance (AMR) profiles, while the Raven assembly of Klebsiella variicola with low-quality reads was the only assembly with an accurate AMR profile among all assemblers and species. All assemblers functioned well for predicting virulence genes using mediocre-quality and real reads, whereas only the Raven assemblies of low-quality reads had accurate numbers of virulence genes. Regarding multilocus sequence typing (MLST), Miniasm/Racon was the most effective assembler for mediocre-quality reads, while only the Raven assemblies of Escherichia coli O157:H7 and K. variicola with low-quality reads showed positive MLST results. Miniasm/Racon and Raven were the best performers for MLST using real reads. The Miniasm/Racon and Raven assemblies showed accurate phylogenetic inference. For the pan-genome analyses, Raven was the strongest assembler for simulated reads, whereas Miniasm/Racon and Raven performed the best for real reads. Overall, the most robust and accurate assembler was Raven, closely followed by Miniasm/Racon.},

issue = {23},

langid = {english},

}

@article{chenBindingHnRNPExonic1999,

urldate = {2022-09-27},

abstract = {In the rat β-tropomyosin (β-TM) gene, exons 6 and 7 are spliced alternatively in a mutually exclusive manner. Exon 6 is included in mRNA encoding nonmuscle TM-1, whereas exon 7 is used in mRNA encoding skeletal muscle β-TM. Previously, we demonstrated that a six nucleotide mutation at the 5′ end of exon 7, designated as ex-1, activated exon 7 splicing in nonmuscle cells. In this study, we show that the activating effect of this mutation is not the result of creating an exonic splicing enhancer (ESE) or disrupting a putative secondary structure. The sequence in exon 7 acts as a bona fide exonic splicing silencer (ESS), which is bound specifically by atrans-acting factor. Isolation and peptide sequencing reveal that this factor is hnRNP H, a member of the heterogeneous nuclear ribonucleoprotein (hnRNP) family. Binding of hnRNP H correlates with the ESS activity. Furthermore, addition of antibodies that specifically recognizes hnRNP H to the splicing reactions or partial depletion of hnRNP H from nuclear extract activates exon 7 splicing in vitro and this effect can be reversed by addition of purified recombinant hnRNP H. These results indicate that hnRNP H participates in exclusion of exon 7 in nonmuscle cells. The involvement of hnRNP H in the activity of an ESS may represent a prototype for the regulation of tissue- and developmental-specific alternative splicing.},

langid = {english},

}

@article{chenDeregulationFCGR2BExpression2001,

issn = {1476-5594},

doi = {10.1038/sj.onc.1204989},

url = {http://dx.doi.org/10.1038/sj.onc.1204989},

}

@article{chenIndolentMantleCell2009,

doi = {10.1182/blood.V114.22.3937.3937},

url = {https://ashpublications.org/blood/article/114/22/3937/76125/Indolent-Mantle-Cell-Lymphoma-A-Distinct-Subgroup},

urldate = {2019-12-21},

}

@article{chenMantaRapidDetection2016,

journaltitle = {Blood},

volume = {111},

number = {4},

}

@article{chenThymidinePhosphorylaseMRNA2009,

abstract = {The cytoplasmic level of heterogeneous nuclear ribonucleoprotein K (hnRNP K) is significantly correlated with the elevated expression of thymidine phosphorylase (TP), and high levels of both proteins are predictive of a poor prognosis in nasopharyngeal carcinoma (NPC). We herein show that TP is highly induced by serum deprivation in NPC cells, and that this is due to an increase in the half-life of the TP mRNA, as shown by nuclear run-on and actinomycin D assays. We further show that the CU-rich element of the TP mRNA directly interacts with hnRNP K, as demonstrated by immunoprecipitation RT–PCR assays, and the nucleus-to-cytoplasm translocation of hnRNP K. Blockade of hnRNP K expression reduces TP expression, suggesting that hnRNP K acts in the upregulation of TP. Mechanistically, both MEK inhibitor and the hnRNP K ERK-phosphoacceptor-site mutant decrease cytoplasmic accumulation of hnRNP K, suggesting that ERK-dependent phosphorylation is critical for TP induction. Furthermore, we found that hnRNP K-mediated TP induction allows NPC cells to resist hypoxia-induced apoptosis. Our results collectively establish the regulation and role of ERK-mediated cytoplasmic accumulation of hnRNP K as an upstream modulator of TP, suggesting that hnRNP K may be an attractive candidate as a future therapeutic target for cancer.},

issue = {17},

langid = {english},

}

@article{chesonOblimersenTreatmentPatients2007,

url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2376092/},

urldate = {2020-09-22},

abstract = {Among adults in Western countries, chronic lymphocytic leukemia (CLL) is the most prevalent form of leukemia. CLL primarily affects the elderly and may be associated with multiple comorbidities. A cure has not been identified, and new treatment options are needed. Expression of Bcl-2 protein is associated with the pathogenesis of CLL and chemotherapy resistance. Oblimersen, a Bcl-2 antisense phosphorothioate oligonucleotide, is being evaluated in patients with CLL and other cancers; trials through Phase III have been completed. In the setting of relapsed/refractory CLL, single-agent oblimersen demonstrates modest activity, whereas the addition of oblimersen to fludarabine/cyclophosphamide significantly improves the rate of complete and nodular partial responses; moreover, these responses are durable and associated with clinical benefit. Oblimersen is more efficacious in relapsed rather than refractory patients. The side effect profile of oblimersen, alone or in combination with standard chemotherapy, is favorable compared with currently available chemotherapies. In the first cycle, an infusion reaction with or without tumor lysis syndrome is uncommon, and transient thrombocytopenia is observed. Catheter-related complications are associated with the need for continuous intravenous infusion of oblimersen over several days; other routes of administration are under clinical investigation. Oblimersen is a promising therapeutic approach for patients with relapsed CLL and should be further evaluated in the front-line setting.},

}

@article{cheungAcquiredTNFRSF14Mutations2010a,

doi = {10.1158/0008-5472.CAN-10-2460},

abstract = {Clinical correlative studies have linked 1p36 deletions with worse prognosis in follicular lymphoma (FL). In this study, we sought to identify the critical gene(s) in this region that is responsible for conferring inferior prognosis. BAC array technology applied to 141 FL specimens detected a minimum region of deletion (MRD) of ∼97 kb within 1p36.32 in 20\% of these cases. Frequent single-nucleotide polymorphism-detected copy-neutral loss of heterozygosity was also found in this region. Analysis of promoter CpGs in the MRD did not reveal differential patterns of DNA methylation in samples that differed in 1p36 status. Exon sequencing of MRD genes identified somatic alterations in the TNFRSF14 gene in 3 of 11 selected cases with matching normal DNA. An expanded cohort consisting of 251 specimens identified 46 cases (18.3\%) with nonsynonymous mutations affecting TNFRSF14. Overall survival (OS) and disease-specific survival (DSS) were associated with the presence of TNFRSF14 mutation in patients whose overall treatment included rituximab. We further showed that inferior OS and DSS were most pronounced in patients whose lymphomas contained both TNFRSF14 mutations and 1p36 deletions after adjustment for the International Prognostic Index [hazard ratios of 3.65 (95\% confidence interval, 1.35-9.878, P=0.011) and 3.19 (95\% confidence interval, 1.06-9.57, P=0.039), respectively]. Our findings identify TNFRSF14 as a candidate gene associated with a subset of FL, based on frequent occurrence of acquired mutations and their correlation with inferior clinical outcomes.},

langid = {english},

}

@article{choiNewImmunostainAlgorithm2009,

journaltitle = {Clin Cancer Res},

volume = {15},

number = {17},

}

@article{chongComprehensiveCharacterizationProgrammed2016,

doi = {10.1182/blood-2015-11-683003},

abstract = {Programmed death ligands (PDLs) are immune-regulatory molecules that are frequently affected by chromosomal alterations in B-cell lymphomas. Although PDL copy-number variations are well characterized, a detailed and comprehensive analysis of structural rearrangements (SRs) and associated phenotypic consequences is largely lacking. Here, we used oligonucleotide capture sequencing of 67 formalin-fixed paraffin-embedded tissues derived from primary B-cell lymphomas and 1 cell line to detect and characterize, at base-pair resolution, SRs of the PDL locus (9p24.1; harboring PDL1/CD274 and PDL2/PDCD1LG2). We describe 36 novel PDL SRs, including 17 intrachromosomal events (inversions, duplications, deletions) and 19 translocations involving BZRAP-AS1, CD44, GET4, IL4R, KIAA0226L, MID1, RCC1, PTPN1 and segments of the immunoglobulin loci. Moreover, analysis of the precise chromosomal breakpoints reveals 2 distinct cluster breakpoint regions (CBRs) within either CD274 (CBR1) or PDCD1LG2 (CBR2). To determine the phenotypic consequences of these SRs, we performed immunohistochemistry for CD274 and PDCD1LG2 on primary pretreatment biopsies and found that PDL SRs are significantly associated with PDL protein expression. Finally, stable ectopic expression of wild-type PDCD1LG2 and the PDCD1LG2-IGHV7-81 fusion showed, in coculture, significantly reduced T-cell activation. Taken together, our data demonstrate the complementary utility of fluorescence in situ hybridization and capture sequencing approaches and provide a classification scheme for PDL SRs with implications for future studies using PDL immune-checkpoint inhibitors in B-cell lymphomas.},

langid = {english},

}

@article{chongHighresolutionArchitecturePartner2018,

urldate = {2022-09-28},

abstract = {p63, a transcription factor and p53 family protein, plays a crucial role in tumor suppression and development of various epithelial tissues. While p63 expression is controlled mostly by post-translational modifications, recent studies indicate that transcriptional and posttranscriptional regulations are essential for proper p63 expression. Here, we investigated the regulation of p63 expression by poly (C)-binding protein 1 (PCBP1, also known as hnRNP-E1 and αCP1). We found that knockdown of PCBP1 decreases the level of p63 transcript and protein. We also found that PCBP1 regulates the stability of p63 mRNA via binding to p63 3’UTR. Additionally, we found that a CU-rich element (CUE) in p63 3′UTR is bound by and responsive to PCBP1. Together, we conclude that PCBP1 regulates p63 expression via mRNA stability.},

langid = {english},

}

@article{choPromoterLncRNAGene2018,

url = {https://www.nature.com/articles/ncomms4078},

urldate = {2018-08-23},

abstract = {Alternative splicing of pre-messenger RNA (mRNA) is a critical stage of gene regulation in response to environmental stimuli. Here we show that DAZAP1, an RNA-binding protein involved in mammalian development and spermatogenesis, promotes inclusion of weak exons through specific recognition of diverse cis-elements. The carboxy-terminal proline-rich domain of DAZAP1 interacts with and neutralizes general splicing inhibitors, and is sufficient to activate splicing when recruited to pre-mRNA. This domain is phosphorylated by the MEK/Erk (extracellular signal-regulated protein kinase) pathway and this modification is essential for the splicing regulatory activity and the nuclear/cytoplasmic translocation of DAZAP1. Using mRNA-seq, we identify endogenous splicing events regulated by DAZAP1, many of which are involved in maintaining cell growth. Knockdown or over-expression of DAZAP1 causes a cell proliferation defect. Taken together, these studies reveal a molecular mechanism that integrates splicing control into MEK/Erk-regulated cell proliferation.},

}

@article{chouHnRNPComponentSplicing1999,

doi = {10.1016/j.ccell.2016.02.009},

url = {https://www.cell.com/cancer-cell/abstract/S1535-6108(16)30043-5},

urldate = {2022-11-23},

}

@article{chungSetNovelConserved1986,

url = {http://onlinelibrary.wiley.com/doi/abs/10.1002/prot.340010302},

urldate = {2022-10-06},

langid = {english},

}

@article{ciborowskiNovelClassII2017,

journaltitle = {Clinica Chimica Acta},

volume = {411},

number = {23-24},

}

@article{colganMechanismRegulationMRNA1997,

url = {http://genesdev.cshlp.org/content/11/21/2755},

urldate = {2022-10-06},

abstract = {A biweekly scientific journal publishing high-quality research in molecular biology and genetics, cancer biology, biochemistry, and related fields},

}

@article{compagnoMutationsMultipleGenes2009a,

abstract = {Diffuse large B-cell lymphoma (DLBCL), the most common form of lymphoma in adulthood, comprises multiple biologically and clinically distinct subtypes including germinal centre B-cell-like (GCB) and activated B-cell-like (ABC) DLBCL. Gene expression profile studies have shown that its most aggressive subtype, ABC-DLBCL, is associated with constitutive activation of the NF-kappaB transcription complex. However, except for a small fraction of cases, it remains unclear whether NF-kappaB activation in these tumours represents an intrinsic program of the tumour cell of origin or a pathogenetic event. Here we show that {$>$}50\% of ABC-DLBCL and a smaller fraction of GCB-DLBCL carry somatic mutations in multiple genes, including negative (TNFAIP3, also called A20) and positive (CARD11, TRAF2, TRAF5, MAP3K7 (TAK1) and TNFRSF11A (RANK)) regulators of NF-kappaB. Of these, the A20 gene, which encodes a ubiquitin-modifying enzyme involved in termination of NF-kappaB responses, is most commonly affected, with approximately 30\% of patients displaying biallelic inactivation by mutations and/or deletions. When reintroduced in cell lines carrying biallelic inactivation of the gene, A20 induced apoptosis and cell growth arrest, indicating a tumour suppressor role. Less frequently, missense mutations of TRAF2 and CARD11 produce molecules with significantly enhanced ability to activate NF-kappaB. Thus, our results demonstrate that NF-kappaB activation in DLBCL is caused by genetic lesions affecting multiple genes, the loss or activation of which may promote lymphomagenesis by leading to abnormally prolonged NF-kappaB responses.},

langid = {english},

pmcid = {PMC2973325},

}

@article{cooperCellsHitClass2019,

doi = {10.1016/j.immuni.2019.07.004},

url = {https://www.cell.com/immunity/abstract/S1074-7613(19)30320-6},

urldate = {2020-05-25},

}

@article{copie-bergmanMYCIGRearrangementsAre2015,

url = {http://www.bloodjournal.org/content/126/22/2466},

urldate = {2019-07-15},

abstract = {Diffuse large B-cell lymphoma (DLBCL) with MYC rearrangement (MYC-R) carries an unfavorable outcome. We explored the prognostic value of the MYC translocation partner gene in a series of MYC-R de novo DLBCL patients enrolled in first-line prospective clinical trials (Groupe d’Etudes des Lymphomes de l’Adulte/Lymphoma Study Association) and treated with rituximab-anthracycline–based chemotherapy. A total of 774 DLBCL cases characterized for cell of origin by the Hans classifier were analyzed using fluorescence in situ hybridization with BCL2, BCL6, MYC, immunoglobulin (IG)K, and IGL break-apart and IGH/MYC, IGK/MYC, and IGL/MYC fusion probes. MYC-R was observed in 51/574 (8.9\%) evaluable DLBCL cases. MYC-R cases were predominantly of the germinal center B-cell–like subtype 37/51 (74\%) with no distinctive morphologic and phenotypic features. Nineteen cases were MYC single-hit and 32 cases were MYC double-hit (MYC plus BCL2 and/or BCL6) DLBCL. MYC translocation partner was an IG gene in 24 cases (MYC-IG) and a non-IG gene (MYC-non-IG) in 26 of 50 evaluable cases. Noteworthy, MYC-IG patients had shorter overall survival (OS) (P = .0002) compared with MYC-negative patients, whereas no survival difference was observed between MYC-non-IG and MYC-negative patients. In multivariate analyses, MYC-IG predicted poor progression-free survival (P = .0051) and OS (P = .0006) independently from the International Prognostic Index and the Hans classifier. In conclusion, we show in this prospective randomized trial that the adverse prognostic impact of MYC-R is correlated to the MYC-IG translocation partner gene in DLBCL patients treated with immunochemotherapy. These results may have an important impact on the clinical management of DLBCL patients with MYC-R who should be routinely characterized according to MYC partner gene. These trials are individually registered at www.clinicaltrials.gov as \#NCT00144807, \#NCT01087424, \#NCT00169143, \#NCT00144755, \#NCT00140660, \#NCT00140595, and \#NCT00135499.},

}

@online{CopyNumberVariations,

title = {Copy Number Variations and Cancer | {{Genome Medicine}} | {{Full Text}}},

url = {https://genomemedicine.biomedcentral.com/articles/10.1186/gm62},

}

@article{courtsRecurrentInactivationPRDM12008,

doi = {10.1097/NEN.0b013e31817dd02d},

abstract = {Primary lymphomas of the CNS (PCNSLs) show molecular features of the late germinal center exit B-cell phenotype and are impaired in their terminal differentiation as indicated by a lack of immunoglobulin class switching. Because the positive regulatory domain I protein with ZNF domain (PRDM1/BLIMP1) is a master regulator of terminal B-cell differentiation into plasma cells, we investigated a series of 21 PCNSLs for the presence of mutations in the PRDM1 gene and alterations in the expression pattern of the PRDM1 protein. Direct sequencing of all coding exons of the PRDM1 gene identified deleterious mutations associated with abrogation of PRDM1 protein expression in 4 of 21 (19\%) PCNSLs. Thus, similar to systemic diffuse large B-cell lymphomas, PRDM1 may be a tumor suppressor in some PCNSL and contribute to lymphomagenesis by impairing terminal differentiation.},

langid = {english},

}

@article{coyleSharedDistinctGenetic2022,

doi = {10.1182/bloodadvances.2021006429},

langid = {english},

pmcid = {PMC9198934},

}

@article{crumpRandomizedComparisonGemcitabine2014,

doi = {10.1200/JCO.2013.53.9593},

abstract = {PURPOSE: For patients with relapsed or refractory aggressive lymphoma, we hypothesized that gemcitabine-based therapy before autologous stem-cell transplantation (ASCT) is as effective as and less toxic than standard treatment. PATIENTS AND METHODS: We randomly assigned 619 patients with relapsed/refractory aggressive lymphoma to treatment with gemcitabine, dexamethasone, and cisplatin (GDP) or to dexamethasone, cytarabine, and cisplatin (DHAP). Patients with B-cell lymphoma also received rituximab. Responding patients proceeded to stem-cell collection and ASCT. Coprimary end points were response rate after two treatment cycles and transplantation rate. The noninferiority margin for the response rate to GDP relative to DHAP was set at 10\%. Secondary end points included event-free and overall survival, treatment toxicity, and quality of life. RESULTS: For the intention-to-treat population, the response rate with GDP was 45.2\%; with DHAP the response rate was 44.0\% (95\% CI for difference, -9.0\% to 6.7\%), meeting protocol-defined criteria for noninferiority of GDP (P = .005). Similar results were obtained in a per-protocol analysis. The transplantation rates were 52.1\% with GDP and 49.3\% with DHAP (P = .44). At a median follow-up of 53 months, no differences were detected in event-free survival (HR, 0.99; stratified log-rank P = .95) or overall survival (HR, 1.03; P = .78) between GDP and DHAP. Treatment with GDP was associated with less toxicity (P {$<$} .001) and need for hospitalization (P {$<$} .001), and preserved quality of life (P = .04). CONCLUSION: For patients with relapsed or refractory aggressive lymphoma, in comparison with DHAP, treatment with GDP is associated with a noninferior response rate, similar transplantation rate, event-free survival, and overall survival, less toxicity and hospitalization, and superior quality of life.},

langid = {english},

}

@article{curryPrognosticImpactCREL2009,

journaltitle = {Journal of Hematopathology},

volume = {2},

number = {1},

}

@article{daiCharacterizationMouseDazap12001,

abstract = {Primary mediastinal B-Cell lymphoma (PMBL) is a recently defined entity comprising \textasciitilde 2-10\% non-Hodgkin lymphomas (NHL). Unlike most NHL subtypes, PMBL lacks recurrent gene rearrangements to serve as biomarkers or betray target genes. While druggable, late chemotherapeutic complications warrant the search for new targets and models. Well characterized tumor cell lines provide unlimited material to serve as preclinical resources for verifiable analyses directed at the discovery of new biomarkers and pathological targets using high throughput microarray technologies. The same cells may then be used to seek intelligent therapies directed at clinically validated targets. Four cell lines have emerged as potential PMBL models: FARAGE, KARPAS-1106P, MEDB-1 and U-2940. Transcriptionally, PMBL cell lines cluster near c(lassical)-HL and B-NHL examples showing they are related but separate entities. Here we document genomic alterations therein, by cytogenetics and high density oligonucleotide/SNP microarrays and parse their impact by integrated global expression profiling. PMBL cell lines were distinguished by moderate chromosome rearrangement levels undercutting cHL, while lacking oncogene translocations seen in B-NHL. In total 61 deletions were shared by two or more cell lines, together with 12 amplifications (≥4x) and 72 homozygous regions. Integrated genomic and transcriptional profiling showed deletions to be the most important class of chromosome rearrangement. Lesions were mapped to several loci associated with PMBL, e.g. 2p15 (REL/COMMD1), 9p24 (JAK2, CD274), 16p13 (SOCS1, LITAF, CIITA); plus new or tenuously associated loci: 2p16 (MSH6), 6q23 (TNFAIP3), 9p22 (CDKN2A/B), 20p12 (PTPN1). Discrete homozygous regions sometimes substituted focal deletions accompanied by gene silencing implying a role for epigenetic or mutational inactivation. Genomic amplifications increasing gene expression or gene-activating rearrangements were respectively rare or absent. Our findings highlight biallelic deletions as a major class of chromosomal lesion in PMBL cell lines, while endorsing the latter as preclinical models for hunting and testing new biomarkers and actionable targets.},

langid = {english},

pmcid = {PMC4657880},

}

@article{davidHnRNPProteinsControlled2010,

abstract = {Cancer cells avidly take up glucose and convert it to lactate while eschewing oxidative phosphorylation. This phenomenon is critical for maximal tumorigenicity, and is in part explained by the almost universal reversion of tumours to the embryonic form of pyruvate kinase, PKM2. Here, David et al. now show that aberrant expression of the splicing factors PTB, hnRNPA1 and hnRNPA2, which are themselves regulated by the c-Myc oncogene, is responsible for the PKM1 to PKM2 switch in cancer. This work adds to our understanding of alternative splicing and its role in cancer cell growth.},

issue = {7279},

langid = {english},

}

@article{daviesComparisonMHGDZsig2023,

doi = {10.1182/bloodadvances.2023010673},

url = {https://doi.org/10.1182/bloodadvances.2023010673},

urldate = {2023-10-17},

}

@article{davisChronicActiveBcellreceptor2010,

journaltitle = {Nature},

volume = {463},

number = {7277},

}

@article{davisConstitutiveNuclearFactor2001,

journaltitle = {J Exp Med},

volume = {194},

number = {12},

}

@article{dawsonAnalysisCirculatingTumor2013,

title = {Analysis of {{Circulating Tumor DNA}} to {{Monitor Metastatic Breast Cancer}}.},

author = {Dawson, Sarah-Jane and Tsui, Dana W Y and Murtaza, Muhammed and Biggs, Heather and Rueda, Oscar M and Chin, Suet-Feung and Dunning, Mark J and Gale, Davina and Forshew, Tim and Mahler-Araujo, Betania and Rajan, Sabrina and Humphray, Sean and Becq, Jennifer and Halsall, David and Wallis, Matthew and Bentley, David and Caldas, Carlos and Rosenfeld, Nitzan},

date = {2013-03},

}

@article{decorsiereEssentialRoleInteraction2011,

urldate = {2022-09-28},

abstract = {Following DNA damage, mRNA 3′-end formation is inhibited, contributing to repression of mRNA synthesis. Here we investigated how DNA-damaged cells accomplish p53 mRNA 3′-end formation when normal mechanisms of pre-mRNA 3′-end processing regulation are inhibited. The underlying mechanism involves the interaction between a G-quadruplex structure located downstream from the p53 cleavage site and hnRNP H/F. Importantly, this interaction is critical for p53 expression and contributes to p53-mediated apoptosis. Our results uncover the existence of a specific rescue mechanism of 3′-end processing regulation allowing stress-induced p53 accumulation and function in apoptosis.},

langid = {english},

}

@article{deebMachineLearningbasedClassification,

journaltitle = {Molecular \& Cellular Proteomics},

volume = {14},

number = {11},