The DOI matches its Crossref record; 78 of the 78 references it cites were found in a registry or an index.
Disruption of KMT2D perturbs germinal center B cell development and promotes lymphomagenesis
Open accessAbstract
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.
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Metadata
- Authors
- Zhang, J., Dominguez-Sola, D., Hussein, S., Lee, J.-E., Holmes, A. B., Bansal, M., Vlasevska, S., Mo, T., Tang, H., Basso, K., Ge, K., Dalla-Favera, R., & Pasqualucci, L.
- Venue
- Nature Medicine
- Published
- 2015-09-14
- Volume
- 21
- Issue
- 10
- Pages
- 1190-1198
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2216217499
- Cited by
- 466
- References
- 78
- FWCI
- 24.09
- Type
- journal article
- Language
- en
- Open access
- green
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