Molecular mechanisms of blast crisis transition and maintenance of leukemic stem cells in chronic myelogenous leukemia

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We show here that Hairy enhancer of split 1 (Hes1) has a role in blast crisis transition of CML. Hes1 is a basic helix-loop-helix transcriptional repressor that affects differentiation and often helps maintain cells in an immature state in various tissues. Also we show that expression of Hes1 immortalizes common myeloid progenitors (CMPs) and granulocyte-macrophage progenitors (GMPs). Whereas these cells did not develop myeloproliferative neoplasms when intravenously administered into irradiated mice, combination of Hes1 and BCR-ABL in both CMPs and GMPs caused a blast crisis of human CML-like disease, resulting in the rapid death of all the recipient mice. Intriguingly, Hes1 was highly expressed in 8 of 20 patients with CML in blast crisis, but not in the chronic phase, and dominant negative Hes1 retarded the growth of some CML cell lines expressing Hes1. These results taken together suggest that our model provides a good model to study mechanisms of the blast crisis transition in CML.