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Leukemia. 2016 Oct;30(10):1993-2001. doi: 10.1038/leu.2016.100. Epub 2016 Apr 27.

Loss-of-function mutations of Dynamin 2 promote T-ALL by enhancing IL-7 signalling.

Author information

1
Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria, Australia.
2
Cell Signalling Unit, Children's Medical Research Institute, Sydney, New South Wales, Australia.
3
Cancer and Haematology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
4
Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid, Madrid, Spain.
5
Department of Medicine, Monash University, Melbourne, Victoria, Australia.
6
Clinical Haematology, Alfred Hospital, Prahran, Victoria, Australia.

Abstract

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 with 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 interleukin (IL)-7 receptor resulting in increased receptor density on the surface of leukemic stem cells. These findings suggest that DNM2 mutations cooperate with T-cell oncogenes by enhancing IL-7 signalling.

PMID:
27118408
DOI:
10.1038/leu.2016.100
[Indexed for MEDLINE]

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