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+@article{mentzPARP14NovelTarget2022,

+ title = {{{PARP14}} Is a Novel Target in {{STAT6}} Mutant Follicular Lymphoma},

+ author = {Mentz, Michael and Keay, William and Strobl, Carolin Dorothea and Antoniolli, Martina and Adolph, Louisa and Heide, Michael and Lechner, Axel and Haebe, Sarah and Osterode, Elisa and Kridel, Robert and Ziegenhain, Christoph and Wange, Lucas Esteban and Hildebrand, Johannes Adrian and Shree, Tanaya and Silkenstedt, Elisabeth and Staiger, Annette M. and Ott, German and Horn, Heike and Szczepanowski, Monika and Richter, Julia and Levy, Ronald and Rosenwald, Andreas and Enard, Wolfgang and Zimber-Strobl, Ursula and family=Bergwelt-Baildon, given=Michael, prefix=von, useprefix=true and Hiddemann, Wolfgang and Klapper, Wolfram and Schmidt-Supprian, Marc and Rudelius, Martina and Bararia, Deepak and Passerini, Verena and Weigert, Oliver},

+ date = {2022-09},

+ journaltitle = {Leukemia},

+ shortjournal = {Leukemia},

+ volume = {36},

+ number = {9},

+ eprint = {35851155},

+ eprinttype = {pmid},

+ pages = {2281--2292},

+ issn = {1476-5551},

+ doi = {10.1038/s41375-022-01641-x},

+ abstract = {The variable clinical course of follicular lymphoma (FL) is determined by the molecular heterogeneity of tumor cells and complex interactions within the tumor microenvironment (TME). IL-4 producing follicular helper T cells (TFH) are critical components of the FL TME. Binding of IL-4 to IL-4R on FL cells activates JAK/STAT signaling. We identified STAT6 mutations (STAT6MUT) in 13\% of FL (N\,=\,33/258), all clustered within the DNA binding domain. Gene expression data and immunohistochemistry showed upregulation of IL-4/STAT6 target genes in STAT6MUT FL, including CCL17, CCL22, and FCER2 (CD23). Functionally, STAT6MUT was gain-of-function by serial replating phenotype in pre-B CFU assays. Expression of STAT6MUT enhanced IL-4 induced FCER2/CD23, CCL17 and CCL22 expression and was associated with nuclear accumulation of pSTAT6. RNA sequencing identified PARP14 -a transcriptional switch and co-activator of STAT6- among the top differentially upregulated genes in IL-4 stimulated STAT6MUT lymphoma cells and in STAT6MUT primary FL cells. Quantitative chromatin immunoprecipitation (qChIP) demonstrated binding of STAT6MUT but not STAT6WT to the PARP14 promotor. Reporter assays showed increased IL-4 induced transactivation activity of STAT6MUT at the PARP14 promotor, suggesting a self-reinforcing regulatory circuit. Knock-down of PARP14 or PARP-inhibition abrogated the STAT6MUT gain-of-function phenotype. Thus, our results identify PARP14 as a novel therapeutic target in STAT6MUT FL.},

+ langid = {english},

+ pmcid = {PMC9417990},

+ keywords = {Humans,Immunohistochemistry,Interleukin-4,Lymphoma B-Cell,Lymphoma Follicular,Poly(ADP-ribose) Polymerases,STAT6 Transcription Factor,Transcriptional Activation,Tumor Microenvironment},

+ file = {/Users/rmorin/Zotero/storage/YQKA9DY3/Mentz et al. - 2022 - PARP14 is a novel target in STAT6 mutant follicula.pdf}

+}

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