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Nat Med. 2015 Oct;21(10):1190-8. doi: 10.1038/nm.3940. Epub 2015 Sep 14.

Disruption of KMT2D perturbs germinal center B cell development and promotes lymphomagenesis.

Author information

1
Institute for Cancer Genetics, Columbia University, New York, New York, USA.
2
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
3
Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
4
Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
5
Department of Systems Biology, Columbia University, New York, New York, USA.
6
Department of Pathology and Cell Biology, Columbia University, New York, New York, USA.
7
Department of Genetics &Development, Columbia University, New York, New York, USA.
8
Department of Microbiology &Immunology, Columbia University, New York, New York, USA.
9
Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York, USA.

Abstract

Mutations in the gene encoding the KMT2D (or MLL2) methyltransferase are highly recurrent and occur early during tumorigenesis in diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL). However, the functional consequences of these mutations and their role in lymphomagenesis are unknown. Here we show that FL- and DLBCL-associated KMT2D mutations impair KMT2D enzymatic activity, leading to diminished global H3K4 methylation in germinal-center (GC) B cells and DLBCL cells. Conditional deletion of Kmt2d early during B cell development, but not after initiation of the GC reaction, results in an increase in GC B cells and enhances B cell proliferation in mice. Moreover, genetic ablation of Kmt2d in mice overexpressing Bcl2 increases the incidence of GC-derived lymphomas resembling human tumors. These findings suggest that KMT2D acts as a tumor suppressor gene whose early loss facilitates lymphomagenesis by remodeling the epigenetic landscape of the cancer precursor cells. Eradication of KMT2D-deficient cells may thus represent a rational therapeutic approach for targeting early tumorigenic events.

PMID:
26366712
PMCID:
PMC5145002
DOI:
10.1038/nm.3940
[Indexed for MEDLINE]
Free PMC Article
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