Hes1 immortalizes committed progenitors and plays a role in blast crisis transition in chronic myelogenous leukemia
Hes1 immortalizes committed progenitors and plays a role in blast crisis transition in chronic myelogenous leukemia
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DOI：
10.1182/blood-2009-05-222836
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发表时间：
2010-04-08
期刊：
影响因子：
20.3
通讯作者：
Chiba, Shigeru
中科院分区：
文献类型：
--
作者：
Nakahara, Fumio;Sakata-Yanagimoto, Mamiko;Chiba, Shigeru
Hairy enhancer of split 1（Hes 1）是一种基本的螺旋-环-螺旋转录抑制因子，其影响分化并且通常帮助维持各种组织中的细胞处于未成熟状态。在这里，我们表明，逆转录病毒表达的Hes 1永生化共同的髓系祖细胞（CMP）和粒细胞-巨噬细胞祖细胞（GMP）的存在下，白细胞介素-3，赋予这些细胞的永久再铺板能力。而这些细胞没有开发骨髓增生性肿瘤时，静脉注射给受辐射的小鼠，Hes 1和BCR-ABL的组合在CMP和GMP引起急性白血病类似的急变的慢性粒细胞白血病（CML），导致受体小鼠迅速死亡。另一方面，如先前所报道的，当在c-Kit阳性、Sca-1阳性和谱系阴性造血干细胞（KSL）中表达时，单独的BCR-ABL引起CML样疾病，而不是定向祖细胞CMP或GMP。来自Hes 1和BCR-ABL表达CMP和GMP的白血病细胞比来自BCR-ABL表达KSL的白血病细胞更不成熟。有趣的是，Hes 1在20例CML急变期患者中的8例中高度表达，但在慢性期则不表达，并且显性阴性Hes 1延缓了一些表达Hes 1的CML细胞系的生长。这些结果表明，Hes 1是CML急变转换的关键分子。（血。2010; 115（14）：2872-2881）
Hairy enhancer of split 1 (Hes1) is a basic helix-loop-helix transcriptional repressor that affects differentiation and often helps maintain cells in an immature state in various tissues. Here we show that retroviral expression of Hes1 immortalizes common myeloid progenitors (CMPs) and granulocyte-macrophage progenitors (GMPs) in the presence of interleukin-3, conferring permanent replating capability on these cells. Whereas these cells did not develop myeloproliferative neoplasms when intravenously administered to irradiated mice, the combination of Hes1 and BCR-ABL in CMPs and GMPs caused acute leukemia resembling blast crisis of chronic myelogenous leukemia (CML), resulting in rapid death of the recipient mice. On the other hand, BCR-ABL alone caused CML-like disease when expressed in c-Kit-positive, Sca-1-positive, and lineage-negative hematopoietic stem cells (KSLs), but not committed progenitors CMPs or GMPs, as previously reported. Leukemic cells derived from Hes1 and BCR-ABL-expressing CMPs and GMPs were more immature than those derived from BCR-ABL-expressing KSLs. 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 suggest that Hes1 is a key molecule in blast crisis transition in CML. (Blood. 2010; 115(14): 2872-2881)