TitleThe histone lysine methyltransferase KMT2D sustains a gene expression program that represses B cell lymphoma development.
Publication TypeJournal Article
Year of Publication2015
AuthorsOrtega-Molina, Ana, Boss Isaac W., Canela Andres, Pan Heng, Jiang Yanwen, Zhao Chunying, Jiang Man, Hu Deqing, Agirre Xabier, Niesvizky Itamar, Lee Ji-Eun, Chen Hua-Tang, Ennishi Daisuke, Scott David W., Mottok Anja, Hother Christoffer, Liu Shichong, Cao Xing-Jun, Tam Wayne, Shaknovich Rita, Garcia Benjamin A., Gascoyne Randy D., Ge Kai, Shilatifard Ali, Elemento Olivier, Nussenzweig Andre, Melnick Ari M., and Wendel Hans-Guido
JournalNat Med
Date Published2015 Oct
KeywordsAnimals, B-Lymphocytes, DNA-Binding Proteins, Gene Expression Regulation, Humans, Lymphoma, B-Cell, Mice, Mice, Knockout, Mutation, Neoplasm Proteins

<p>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.</p>

Alternate JournalNat Med
PubMed ID26366710
PubMed Central IDPMC4676270
Grant ListR01 CA190384 / CA / NCI NIH HHS / United States
1R01CA19038-01 / CA / NCI NIH HHS / United States
R01 CA187109 / CA / NCI NIH HHS / United States
R01 CA183876 / CA / NCI NIH HHS / United States
DP2OD007447 / OD / NIH HHS / United States
R01CA150265 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
P30 CA060553 / CA / NCI NIH HHS / United States
/ / Intramural NIH HHS / United States
R01GM110174 / GM / NIGMS NIH HHS / United States
DP2 OD007447 / OD / NIH HHS / United States
R01 GM110174 / GM / NIGMS NIH HHS / United States
R0A183876-01 / / PHS HHS / United States
R01 CA150265 / CA / NCI NIH HHS / United States
R01CA187109 / CA / NCI NIH HHS / United States