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

CS Tremblay, FC Brown, M Collett, J Saw, SK Chiu, SE Sonderegger, SE Lucas, R Alserihi, N Chau, ML Toribio, MP McCormack, M Chircop, PJ Robinson, SM Jane, DJ Curtis

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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 languageEnglish
Pages (from-to)1993-2001
Number of pages9
JournalLeukemia
Volume30
Issue number10
DOIs
Publication statusPublished - 1 Oct 2016

Cite this

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. (2016). Loss-of-function mutations of Dynamin 2 promote T-ALL by enhancing IL-7 signalling. Leukemia, 30(10), 1993-2001. https://doi.org/10.1038/leu.2016.100