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

我们在这里证明了Split 1的毛发增强子(Hes1)在CML的急变过程中发挥了作用。HES1是一种基本的螺旋-环-螺旋转录抑制因子，它影响细胞的分化，通常有助于维持各种组织中的细胞处于未成熟状态。我们还表明，Hes1的表达使普通髓系祖细胞(CMPS)和粒细胞-巨噬细胞祖细胞(GMP)永生化。当这些细胞静脉注射到受照射的小鼠体内时，没有发生骨髓增殖性肿瘤，但Hes1和bcr-abl在CMPS和GMPs中的结合导致了人类CML样病的爆发危机，导致所有受体小鼠迅速死亡。有趣的是，Hes1在20例急变期CML患者中有8例高表达，但在慢性期不表达，显性阴性Hes1抑制了一些表达Hes1的CML细胞系的生长。这些结果表明，我们的模型为研究慢性粒细胞白血病的爆炸危机转变机制提供了一个很好的模型。

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.