Aggressive myeloid leukemia formation is directed by the Musashi 2/Numb pathway

Chronic myeloid leukemia (CML) progresses from a chronic phase to a deadly blast crisis phase. While it is known that BCR-ABL initiates the disease and that secondary molecular and genetic abnormalities likely contribute to progression of the disease to blast crisis, details regarding the mechanism(s) of blast phase progression are lacking. Two recent reports identify Musashi 2 (Msi2) as a key regulator in the progression of CML from the chronic phase to blast crisis. These reports demonstrated that the cell fate determination protein, Numb, was downregulated in blast crisis CML and that exogenous expression of Numb inhibited leukemogenesis. Correspondingly, Msi2 was shown to be upregulated in blast crisis CML and to negatively regulate expression of Numb. Exogenous expression of Msi2 enhanced the formation of an aggressive immature leukemia induced by BCR-ABL. High expression of Msi2 was also found in leukemic cells of AML patients and elevated Msi2 expression was shown to associate with poor prognosis in both AML and CML. These reports together highlight the apparent role of the Musashi-Numb pathway in regulating the formation of aggressive myeloid leukemia, and thus provide a potential molecular mechanism for the transition of chronic phase CML to the deadly blast crisis. Importantly, this work suggests this pathway may provide targets for future therapies that are desperately needed for aggressive forms of myeloid leukemia.