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

• Published in: Nature medicine Vol. 21; no. 10; pp. 1190 - 1198
• Main Authors: Zhang, Jiyuan, Dominguez-Sola, David, Hussein, Shafinaz, Lee, Ji-Eun, Holmes, Antony B, Bansal, Mukesh, Vlasevska, Sofija, Mo, Tongwei, Tang, Hongyan, Basso, Katia, Ge, Kai, Dalla-Favera, Riccardo, Pasqualucci, Laura
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.10.2015; Nature Publishing Group
• Subjects: 13/106; 13/31; 13/51; 14/63; 38/22; 38/23; 38/39; 38/61; 38/70; 38/71; 38/77; 38/90; 49; 49/105; 49/39; 49/90; 631/337/100/2285; 631/67/1990/291/1621/1915; 64/60; 96/109; Animals; B cells; B-Lymphocytes - pathology; Biomedicine; Cancer; Cancer Research; Cell Proliferation; Development and progression; DNA Methylation; DNA-Binding Proteins - genetics; Enzymatic activity; Epigenesis, Genetic; Gene mutations; Gene Silencing; Genes; Genetic aspects; Germinal Center - cytology; Humans; Infectious Diseases; Lymphoma; Lymphoma, Large B-Cell, Diffuse - etiology; Lymphoma, Large B-Cell, Diffuse - genetics; Lymphomas; Metabolic Diseases; Methylation; Mice; Molecular Medicine; Mutation; Mutation, Missense; Neoplasm Proteins - genetics; Neurosciences; Physiological aspects; Transcription, Genetic; Tumors; United States
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/nm.3940

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.