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 language | English (US) |
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Pages (from-to) | 1199-1208 |
Number of pages | 10 |
Journal | Nature Medicine |
Volume | 21 |
Issue number | 10 |
DOIs | |
State | Published - Oct 1 2015 |
Funding
We thank E. Oricchio (MSKCC), V. Sanghvi (MSKCC), M. Boice (MSKCC), W. Beguelin and M. del Pilar Dominguez Rodriguez (Weill Cornell Medical College) for advice and reagents. Thanks to E. de Stanchina and all of the members of the MSK Antitumor assessment core for technical assistance with mice, the MSK Laboratory of Comparative Pathology, the MSK Flow Cytometry and MSK Molecular Cytology cores, H. Hagenau for Southern blot analysis and B. Sleckman for IgκIII probe. A.O.-M. is supported by funding from The Leukemia & Lymphoma Society. H.G.W. is supported by the American Cancer Society grant RSG-13-048-01-LIB, the Lymphoma Research Foundation, Cycle for Survival, W.H. Goodwin and A. Goodwin and the Commonwealth Foundation for Cancer Research, the Center for Experimental Therapeutics at Memorial Sloan Kettering Cancer Center, US National Institutes of Health (NIH) grants RO1CA183876-01 and 1R01CA19038-01 and Core Grant P30 CA008748. H.G.W. is a Scholar of the Leukemia and Lymphoma Society. A.M.M. is supported by NIH grant R01CA187109, the Chemotherapy Foundation and is a Scholar of the Burroughs Wellcome Foundation. I.W.B. is supported by a Sass Foundation Post-doctoral Fellowship award. B.A.G. acknowledges funding from an NIH Innovator grant (DP2OD007447) from the Office of the Director and NIH grant R01GM110174. A.S.H. is supported by NIH grant R01CA150265. The work in the K.G. laboratory was supported by the Intramural Research Program of the NIDDK, NIH. The work in the A.N. laboratory was supported by the Intramural Research Program of the NIH, the National Cancer Institute, the Center for Cancer Research, a Department of Defense grant (BCRP DOD Idea Expansion Award, grant 11557134) and the Alex Lemonade Stand Foundation Award.
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology