The histone lysine methyltransferase KMT2D sustains a gene expression program that represses B cell lymphoma development

Ana Ortega-Molina, Isaac W. Boss, Andres Canela, Heng Pan, Yanwen Jiang, Chunying Zhao, Man Jiang, Deqing Hu, Xabier Agirre, Itamar Niesvizky, Ji Eun Lee, Hua Tang Chen, Daisuke Ennishi, David W. Scott, Anja Mottok, Christoffer Hother, Shichong Liu, Xing Jun Cao, Wayne Tam, Rita ShaknovichBenjamin A. Garcia, Randy D. Gascoyne, Kai Ge, Ali Shilatifard, Olivier Elemento, Andre Nussenzweig, Ari M. Melnick, Hans Guido Wendel

Research output: Contribution to journalArticle

156 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1199-1208
Number of pages10
JournalNature Medicine
Volume21
Issue number10
DOIs
Publication statusPublished - Oct 1 2015
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    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., ... Wendel, H. G. (2015). The histone lysine methyltransferase KMT2D sustains a gene expression program that represses B cell lymphoma development. Nature Medicine, 21(10), 1199-1208. https://doi.org/10.1038/nm.3943