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

• Published in: Leukemia Vol. 30; no. 10; pp. 1993 - 2001
• Main Authors: Tremblay, C S, Brown, F C, Collett, M, Saw, J, Chiu, S K, Sonderegger, S E, Lucas, S E, Alserihi, R, Chau, N, Toribio, M L, McCormack, M P, Chircop, M, Robinson, P J, Jane, S M, Curtis, D J
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-10-2016; Nature Publishing Group
• Subjects: 13/2; 13/21; 14/19; 631/208/68; 631/67/1990/283/2125; 631/67/395; 631/67/71; 631/80/86; 82/80; 96/100; 96/109; 96/31; 96/95; Acute lymphoblastic leukemia; Acute lymphocytic leukemia; Adaptor Proteins, Signal Transducing - genetics; Anemia; Animals; Blood diseases; Cancer Research; Cellular signal transduction; Clathrin; Critical Care Medicine; Crystal structure; Cytokines; Dynamin; Dynamin II - genetics; Endocytosis; Endocytosis - genetics; Ethyl nitrosourea; Gene mutation; Genetic aspects; Genetic screening; GTP Phosphohydrolases - metabolism; Hematology; Heterozygotes; Humans; Intensive; Interleukin 7; Interleukin-7 - metabolism; Internal Medicine; Kinases; Leukemia; Leukemia, T-Cell - etiology; Leukemia, T-Cell - genetics; Leukemia, T-Cell - metabolism; Ligands; LIM Domain Proteins - genetics; Lymphatic leukemia; Lymphocytes T; Medical research; Medicine; Medicine & Public Health; Mice; Mutants; Mutation; Oncogenes; Oncology; original-article; Pathogenesis; Phenotypes; Receptor density; Receptors; Signal Transduction; Signaling; Stem cell transplantation; Stem cells; Transgenic mice; Australia; Victoria Australia
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2016.100

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 (
Dnm2
V265G
) 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
Dnm2
V265G
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.