Projects per year
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.
Original language | English |
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Pages (from-to) | 1993-2001 |
Number of pages | 9 |
Journal | Leukemia |
Volume | 30 |
Issue number | 10 |
DOIs | |
Publication status | Published - 1 Oct 2016 |
Projects
- 2 Finished
-
The bHLH transcription factor LYL1 in normal and leukemic hematopoiesis
Curtis, D., McCormack, M. P. & Pimanda, J.
National Health and Medical Research Council (NHMRC) (Australia)
1/01/13 → 31/12/15
Project: Research
-
Mechanism of oncogene collaboration in T cell leukemia
Tremblay, C.
Canadian Cancer Society Research Institute
16/12/11 → 30/06/12
Project: Research