A team led by Tannishtha Reya focused on a signature trait of blast crisis — a block in cellular differentiation leading to an accumulation of immature cells. Reya and colleagues reasoned that, in these cells, the transition to blast crisis might rely on the attenuation of normal differentiation cues. To test this theory, her group modelled the chronic and blast crisis phases of CML by transplanting irradiated recipient animals with haematopoietic stem cells that were transduced with BCR–ABL alone (chronic phase) or BCR–ABL together with NUP98–HOXA9 (blast crisis). Armed with these tools, they showed that the RNA binding protein Musashi 2 (MSI2) was dramatically upregulated during blast crisis compared with chronic phase disease. This was a compelling result given the known role of MSI2 as a regulator of asymmetric division in stem and progenitor cells, but was it actually required for progression to blast crisis? Reya and colleagues turned to mice harbouring a targeted disruption in Msi2 and noted impaired leukaemic growth in vivo. Next, short hairpin RNA against Msi2 was introduced into established blast crisis cells, resulting in decreased disease propagation in recipient mice. These results suggest a fundamental requirement for MSI2 in the establishment and maintenance of blast crisis.
During development, MSI2 represses NUMB, a key regulator of cell commitment and differentiation, so the authors asked whether this was also the case in CML. Accordingly, NUMB levels were significantly downregulated at blast crisis compared with chronic phase, and increased when Msi2 expression was inhibited. Crucially, forced expression of NUMB in BCR–ABL; NUP98–HOXA9-transduced cells attenuated disease progression in vivo, and leukaemias that did develop were of a more differentiated phenotype. So, perturbations of the MSI2–NUMB axis in CML disrupts the equilibrium between the differentiated and undifferentiated states, and this propels the disease towards blast crisis.
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