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Nat Med. 2015 Oct;21(10):1199-208. doi: 10.1038/nm.3943. Epub 2015 Sep 14.

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

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Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, USA.
Division of Hematology-Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York, USA.
Department of Pharmacology, Weill Cornell Medical College, New York, New York, USA.
Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York, USA.
Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, Illinois, USA.
Area de Oncología, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Pamplona, Spain.
Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
Epigenetics Program, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York, USA.


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.

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