The histone lysine methyltransferase KMT2D sustains a gene expression program that represses B cell lymphoma development Journal Article
| Authors: | Ortega Molina, A.; Boss, I. W.; Canela, A.; Pan, H.; Jiang, Y.; Zhao, C.; Jiang, M.; Hu, D.; Agirre, X.; Niesvizky, I.; Lee, J. E.; Chen, H. T.; Ennishi, D.; Scott, D. W.; Mottok, A.; Hother, C.; Liu, S.; Cao, X. J.; Tam, W.; Shaknovich, R.; Garcia, B. A.; Gascoyne, R. D.; Ge, K.; Shilatifard, A.; Elemento, O.; Nussenzweig, A.; Melnick, A. M.; Wendel, H. G. |
| Article Title: | The histone lysine methyltransferase KMT2D sustains a gene expression program that represses B cell lymphoma development |
| Abstract: | The gene encoding the lysine-specific histone methyltransferase KMT2D has emerged as one of the most frequently mutated genes in follicular lymphoma and diffuse large B cell lymphoma; however, the biological consequences of KMT2D mutations on lymphoma development are not known. Here we show that KMT2D functions as a bona fide tumor suppressor and that its genetic ablation in B cells promotes lymphoma development in mice. KMT2D deficiency also delays germinal center involution and impedes B cell differentiation and class switch recombination. Integrative genomic analyses indicate that KMT2D affects methylation of lysine 4 on histone H3 (H3K4) and expression of a set of genes, including those in the CD40, JAK-STAT, Toll-like receptor and B cell receptor signaling pathways. Notably, other KMT2D target genes include frequently mutated tumor suppressor genes such as TNFAIP3, SOCS3 and TNFRSF14. Therefore, KMT2D mutations may promote malignant outgrowth by perturbing the expression of tumor suppressor genes that control B cell-activating pathways. © 2015 Nature America, Inc. All rights reserved. |
| Keywords: | controlled study; unclassified drug; gene mutation; nonhuman; animal cell; mouse; animal tissue; gene targeting; gene expression; animal experiment; animal model; cell differentiation; dna methylation; b lymphocyte; tumor suppressor gene; b cell lymphoma; germinal center; genetic recombination; janus kinase; histone h3; genomics; tumor growth; cell activation; involution; toll like receptor; lysine; stat protein; histone lysine methyltransferase; cd40 antigen; b lymphocyte receptor; female; priority journal; article; histone lysine methyltransferase kmt2d |
| Journal Title: | Nature Medicine |
| Volume: | 21 |
| Issue: | 10 |
| ISSN: | 1078-8956 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2015-10-01 |
| Start Page: | 1199 |
| End Page: | 1208 |
| Language: | English |
| DOI: | 10.1038/nm.3943 |
| PROVIDER: | scopus |
| PUBMED: | 26366710 |
| PMCID: | PMC4676270 |
| DOI/URL: | |
| Notes: | Export Date: 2 November 2015 -- Source: Scopus |
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