Aggressive myeloid leukemia formation is directed by the musashi 2/numb pathway
Aggressive myeloid leukemia formation is directed by the musashi 2/numb pathway
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DOI：
10.4161/cbt.10.10.14010
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发表时间：
2010-11-15
影响因子：
3.6
通讯作者：
Reuther, Gary W.
中科院分区：
文献类型：
--
作者：
Griner, Lori N.;Reuther, Gary W.
慢性粒细胞白血病（CML）从慢性期发展到致命的急变期。虽然已知BCR-ABL启动疾病，继发性分子和遗传异常可能导致疾病进展为急变，但缺乏关于急变期进展机制的详细信息。最近的两份报告将Musashi 2（Msi 2）确定为CML从慢性期到急变期进展的关键调节因子。这些报道表明，细胞命运决定蛋白Numb在急变期CML中下调，并且外源性表达Numb抑制白血病发生。相应地，Msi 2在急变期CML中表达上调，并负调节Numb的表达。Msi 2的外源性表达可促进BCR-ABL诱导的侵袭性未成熟白血病的形成，在AML患者的白血病细胞中也发现Msi 2的高表达，并且Msi 2的高表达与AML和CML的不良预后相关。这些报告共同强调了Musashi-Numb通路在调节侵袭性髓系白血病形成中的明显作用，从而为慢性期CML向致命急变的过渡提供了潜在的分子机制。重要的是，这项工作表明，这一途径可能为未来的治疗提供靶点，这些治疗是侵袭性骨髓性白血病迫切需要的。
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.