Heterozygous Mutation Of Dynamin 2 Expands The Pool Of IL-7 Responsive Leukemic Stem Cells In T-Cell Acute Lymphoblastic Leukemia

Early thymocyte progenitor T-cell acute lymphoblastic leukemia (ETP-ALL) is a poor prognosis malignancy that has a distinct genetic basis characterized by activating mutations of the IL-7 signaling pathway. Recurrent mutations spanning Dynamin 2 (Dnm2), a gene encoding a large GTPase required for clathrin-mediated endocytosis, have been identified in ETP-ALL although why these mutations are enriched in ETP-ALL remains obscure. We have utilized the Lmo2 transgenic mouse model to define the role of DNM2 mutations in ETP-ALL. Sequencing of 11 cases of Lmo2-derived T-ALL identified two novel Dnm2 mutations, a frameshift (Serine126fs) and a premature stop (Isoleucine135stop) mutation within the GTPase domain, which confirmed the relevance of this mouse model for studying Dnm2 mutations. We mated Lmo2 mice with mice carrying a germ-line missense mutation of Dnm2 in the GTPase domain (V235G), which impairs GTPase activity. This Dnm2 mutation had two important biologic effects on Lmo2-derived T-ALL: an increased penetrance (90% compared with 50% by 12 months of age; p<0.05) and a more immature phenotype (DN1-3 compared with ISP8). To address the mechanism of these effects, we examined the phenotype and expression profile of early leukemic stem cells harboring the Dnm2 mutation. The major abnormality was an expansion of IL-7 responsive leukemic stem cells with increased proliferation and survival. Intriguingly, the presence of Dnm2 mutations sensitized leukemic cells to killing by a small molecule inhibitor of Dnm2. Together, our data provide the first experimental evidence that Dnm2 mutations are enriched in ETP-ALL by expanding the pool of IL-7 responsive leukemic stem cells. Furthermore, our data supports further testing of Dynamin inhibitors in this subset of poor prognosis T-ALL.