Myeloid leukemia development in c-Cbl RING finger mutant mice is dependent on FLT3 signaling.

Although myeloid leukemias are primarily caused by leukemic stem cells, the molecular basis of their transformation remains largely unknown. Here, by analyzing mice with a mutation in the RING finger domain of c-Cbl, we show that the E3 ubiquitin ligase activity of c-Cbl is required to restrict myeloid leukemia development. These mice develop a myeloproliferative disease which progresses to leukemia and involves hematopoietic progenitors that exhibit augmented FLT3 signaling. Suppressing this signaling through matings with FLT3 ligand knockout mice prevents leukemia development. We also observe enhanced c-Kit, Akt and Erk activity, and deregulated expression of leukemia-associated transcription factors in hematopoietic progenitors. The characterization of these perturbations provides direction for therapeutics that may aid the treatment of patients with c-Cbl mutations.