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

我们发现分裂1毛增强子（Hes1）在CML细胞危象转变中起作用。Hes1是一种基本的螺旋-环-螺旋转录抑制因子，在各种组织中影响分化并经常帮助维持细胞处于未成熟状态。我们还发现，Hes1的表达可以使普通髓系祖细胞（CMPs）和粒细胞-巨噬细胞祖细胞（gmp）永生化。然而，这些细胞在静脉注射到辐照小鼠体内时没有发生骨髓增殖性肿瘤，但在cmp和gmp中，Hes1和BCR-ABL的结合引起了人类cml样疾病的爆炸危机，导致所有受体小鼠迅速死亡。有趣的是，Hes1在20例CML患者中有8例在母细胞危象中高表达，但在慢性期没有高表达，并且显性阴性Hes1阻滞了一些表达Hes1的CML细胞系的生长。这些结果表明，我们的模型为研究CML中爆炸危机转变的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.