Loss-of-function mutations of Dynamin 2 promote T-ALL by enhancing IL-7 signalling.
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 Dnm2V265Gmice 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.
Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria, Australia.
C S
CS
Tremblay
Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria, Australia.
F C
FC
Brown
Cell Signalling Unit, Children's Medical Research Institute, Sydney, New South Wales, Australia.
M
M
Collett
Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria, Australia.
J
J
Saw
Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria, Australia.
S K
SK
Chiu
Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria, Australia.
S E
SE
Sonderegger
Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria, Australia.
S E
SE
Lucas
Cancer and Haematology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
R
R
Alserihi
Cell Signalling Unit, Children's Medical Research Institute, Sydney, New South Wales, Australia.
N
N
Chau
Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid, Madrid, Spain.
M L
ML
Toribio
Cancer and Haematology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
M P
MP
McCormack
Cell Signalling Unit, Children's Medical Research Institute, Sydney, New South Wales, Australia.
M
M
Chircop
Cell Signalling Unit, Children's Medical Research Institute, Sydney, New South Wales, Australia.
P J
PJ
Robinson
Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria, Australia.|Department of Medicine, Monash University, Melbourne, Victoria, Australia.|Clinical Haematology, Alfred Hospital, Prahran, Victoria, Australia.
S M
SM
Jane
Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria, Australia.|Clinical Haematology, Alfred Hospital, Prahran, Victoria, Australia.
D J
DJ
Curtis
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000818:Animals; D034285:Dynamin II / Q000235:genetics*; D004705:Endocytosis / Q000235:genetics; D020558:GTP Phosphohydrolases / Q000378:metabolism; D006801:Humans; D015851:Interleukin-7 / Q000378:metabolism*; D060588:LIM Domain Proteins / Q000235:genetics; D015458:Leukemia, T-Cell / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009154:Mutation; D009857:Oncogenes; D015398:Signal Transduction
D048868:Adaptor Proteins, Signal Transducing; D015851:Interleukin-7; D060588:LIM Domain Proteins; C513188:Lmo2 protein, mouse; D020558:GTP Phosphohydrolases; D034285:Dynamin II