CD79B.md
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# CD79B
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## Overview
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-CD79B mutations significantly contribute to the pathogenesis of DLBCL by enhancing BCR signaling and promoting tumor survival. These mutations, especially when co-occurring with MYD88 mutations, define a unique molecular subtype.<sup>1</sup> This has clinical and therapeutic implications as it may contribute sensitivity to BTK inhibitors. In an inducible mouse model of MYD88-driven DLBCL, CD79B mutations did not accelerate lymphomagenesis but demonstrated an increased sensitivity to pharmacological BTK inhibition.<sup>2</sup> In a retrospective analysis, younger patients with MCD DLBCL that were treated with ibrutinib had significantly better outcomes.<sup>3</sup> The most common hotspot mutation in CD79B is at the tyrosine residue 196 (Y196). This and other common mutations primarily occur in the immunoreceptor tyrosine-based activation motif (ITAM) domain and prevent the negative regulatory feedback provided by Lyn kinase thereby enhancing BCR signaling.
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+CD79B mutations significantly contribute to the pathogenesis of DLBCL by enhancing BCR signaling and promoting tumor survival.
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+These mutations, especially when co-occurring with MYD88 mutations, define a unique molecular subtype.[@wrightProbabilisticClassificationTool2020]
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+This has clinical and therapeutic implications as it may contribute sensitivity to BTK inhibitors.
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+In an inducible mouse model of MYD88-driven DLBCL, CD79B mutations did not accelerate lymphomagenesis but demonstrated an increased sensitivity to pharmacological BTK inhibition.[@flumannInducibleCd79bMutation2024]
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+In a retrospective analysis, younger patients with MCD DLBCL that were treated with ibrutinib had significantly better outcomes.[@wilsonEffectIbrutinibRCHOP2021b]
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+The most common hotspot mutation in CD79B is at the tyrosine residue 196 (Y196).
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+This and other common mutations primarily occur in the immunoreceptor tyrosine-based activation motif (ITAM) domain and prevent the negative regulatory feedback provided by Lyn kinase thereby enhancing BCR signaling.
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## History
morinlab.bib
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+@article{wilsonEffectIbrutinibRCHOP2021b,
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+ title = {Effect of Ibrutinib with {{R-CHOP}} Chemotherapy in Genetic Subtypes of {{DLBCL}}},
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+ author = {Wilson, Wyndham H. and Wright, George W. and Huang, Da Wei and Hodkinson, Brendan and Balasubramanian, Sriram and Fan, Yue and Vermeulen, Jessica and Shreeve, Martin and Staudt, Louis M.},
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+ date = {2021-12-13},
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+ journaltitle = {Cancer Cell},
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+ shortjournal = {Cancer Cell},
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+ volume = {39},
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+ number = {12},
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+ eprint = {34739844},
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+ eprinttype = {pmid},
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+ pages = {1643-1653.e3},
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+ issn = {1878-3686},
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+ doi = {10.1016/j.ccell.2021.10.006},
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+ 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.},
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+ langid = {english},
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+ pmcid = {PMC8722194},
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+ keywords = {ABC DLBCL,Adenine,Aged,Antineoplastic Combined Chemotherapy Protocols,BTK inhibitor,cancer genomics,CD79B,Cyclophosphamide,Doxorubicin,Female,Humans,Lymphoma Large B-Cell Diffuse,Male,memory B cell,Middle Aged,MYD88,NOTCH1,Piperidines,precision medicine,Prednisone,Rituximab,Vincristine},
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+ file = {/Users/rmorin/Zotero/storage/UNL9EC8N/Wilson et al. - 2021 - Effect of ibrutinib with R-CHOP chemotherapy in ge.pdf}
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+}
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+
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+@article{flumannInducibleCd79bMutation2024,
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+ title = {An Inducible {{Cd79b}} Mutation Confers Ibrutinib Sensitivity in Mouse Models of {{Myd88-driven}} Diffuse Large {{B-cell}} Lymphoma},
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+ author = {Flümann, Ruth and Hansen, Julia and Meinel, Jörn and Pfeiffer, Pauline and Goldfarb Wittkopf, Hannah and Lütz, Anna and Wirtz, Jessica and Möllmann, Michael and Zhou, Tanja and Tabatabai, Areya and Lohmann, Tim and Jauch, Maximilian and Beleggia, Filippo and Pelzer, Benedikt and Ullrich, Fabian and Höfmann, Svenja and Arora, Aastha and Persigehl, Thorsten and Büttner, Reinhard and family=Tresckow, given=Bastian, prefix=von, useprefix=true and Klein, Sebastian and Jachimowicz, Ron D. and Reinhardt, Hans Christian and Knittel, Gero},
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+ date = {2024-03-12},
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+ journaltitle = {Blood Advances},
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+ shortjournal = {Blood Adv},
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+ volume = {8},
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+ number = {5},
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+ eprint = {38060829},
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+ eprinttype = {pmid},
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+ pages = {1063--1074},
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+ issn = {2473-9537},
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+ doi = {10.1182/bloodadvances.2023011213},
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+ 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.},
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+ langid = {english},
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+ pmcid = {PMC10907402},
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+ keywords = {Adenine,Animals,Lymphoma Large B-Cell Diffuse,Mice,Mutation,Myeloid Differentiation Factor 88,Piperidines,Proto-Oncogene Proteins c-bcl-2},
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+ file = {/Users/rmorin/Zotero/storage/345JS4JJ/Flümann et al. - 2024 - An inducible Cd79b mutation confers ibrutinib sens.pdf}
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+}
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+
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@article{mandatoAbstractA38Cd702022,
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title = {Abstract {{A38}}: {{Cd70}} Genetic Perturbation Limits the Development of an Effective {{CD8}}+ {{T-cell}} Immune Response to {{Bcl6-driven}} Diffuse Large {{B-cell}} Lymphoma},
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shorttitle = {Abstract {{A38}}},