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Disruption of KMT2D perturbs germinal center B cell development and promotes lymphomagenesis
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Disruption of KMT2D perturbs germinal center B cell development and promotes lymphomagenesis
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Journal Article
Disruption of KMT2D perturbs germinal center B cell development and promotes lymphomagenesis
2015
Overview
Two studies demonstrate that the methyltransferase KMT2D, which is recurrently mutated in several types of human B cell lymphoma, suppresses tumorigenesis by altering the epigenetic landscape of B cells;
Kmt2d
deletion in mice perturbs normal B cell development.
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.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
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/ 38/70
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/ 49/90
/ 64/60
/ 96/109
/ Animals
/ B cells
/ Cancer
/ DNA-Binding Proteins - genetics
/ Genes
/ Humans
/ Lymphoma
/ Lymphoma, Large B-Cell, Diffuse - etiology
/ Lymphoma, Large B-Cell, Diffuse - genetics
/ Mice
/ Mutation
/ Neoplasm Proteins - genetics
/ Tumors
