Loss-of-function mutations of Dynamin 2 promote T-ALL by enhancing IL-7 signalling
- Tremblay, CS; Brown, FC; Collett, M; Saw, J; Chiu, SK; Sonderegger, SE; Lucas, SE; Alserihi, R; Chau, N; Toribio, ML; McCormack, MP; Chircop, M; Robinson, PJ; Jane, SM; Curtis, DJ;
Publication Year 2016-04-27, Volume 30, Issue #10, Page 1993-2001
- Journal Title
- Publication Type
- Journal Article
- Mutations in the DYNAMIN2 (DNM2) gene are frequently detected in human acute T-cell lymphoblastic leukemia (T-ALL), although the mechanisms linking these mutations to disease pathogenesis remain unknown. Using an ENU-based forward genetic screen for mice with erythroid phenotypes, we identified a heterozygous mouse line carrying a mutation in the GTPase domain of Dnm2 (Dnm2V265G) that induced a microcytic anemia. In vitro assays using the V265G mutant demonstrated loss of GTPase activity and impaired endocytosis that was comparable to other DNM2 mutants identified in human T-ALL. To determine the effects of DNM2 mutations in T-ALL, we bred the Dnm2V265G mice with the Lmo2 transgenic mouse model of T-ALL. Heterozygous Dnm2 mutants lacking the Lmo2 transgene displayed normal T-cell development, and did not develop T-ALL. In contrast, compound heterozygotes displayed an accelerated onset of T-ALL compared to mice carrying the Lmo2 oncogene alone. The leukemias from these mice exhibited a more immature immunophenotype and an expansion in leukemic stem cell numbers. Mechanistically, the Dnm2 mutation impaired clathrin-mediated endocytosis of the IL-7 receptor resulting in increased receptor density on the surface of leukemic stem cells. These findings suggest that DNM2 mutations co-operate with T-cell oncogenes by enhancing IL-7 signalling.Leukemia accepted article preview online, 27 April 2016. doi:10.1038/leu.2016.100.
- WEHI Research Division(s)
- Cancer And Haematology
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- Publisher's Version
- NHMRC Grants
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- Refer to copyright notice on published article.
Creation Date: 2016-06-15 08:01:04Last Modified: 2018-07-05 09:51:20