| First Author | Zhang J | Year | 2015 |
| Journal | Nat Med | Volume | 21 |
| Issue | 10 | Pages | 1190-8 |
| PubMed ID | 26366712 | Mgi Jnum | J:228913 |
| Mgi Id | MGI:5749630 | Doi | 10.1038/nm.3940 |
| Citation | Zhang J, et al. (2015) Disruption of KMT2D perturbs germinal center B cell development and promotes lymphomagenesis. Nat Med 21(10):1190-8 |
| abstractText | 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. |
