Bmi1 is essential for leukemic reprogramming of myeloid progenitor cells
Bmi1 is essential for leukemic reprogramming of myeloid progenitor cells
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DOI：
10.1038/leu.2011.85
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发表时间：
2011-08-01
期刊：
影响因子：
11.4
通讯作者：
Iwama, A.
中科院分区：
文献类型：
--
作者：
Yuan, J.;Takeuchi, M.;Iwama, A.
多梳族蛋白（polycomb group，PcG），尤其是Bmi 1，在维持白血病干细胞（leukemic stem cells，LSC）的自我更新能力中起着重要作用。尽管已知它们在LSC中的主要靶点之一是Ink 4a/Arf肿瘤抑制基因位点，但PcG蛋白在靶细胞白血病重编程为LSC中的作用尚未得到很好的表征。在这项研究中，Bmi 1（-/-）粒细胞/巨噬细胞祖细胞（GMP）转化白血病融合基因MLL-AF 9。虽然Bmi 1在体外对GMP永生化不是必需的，但Bmi 1（-/-）细胞显示出增强的分化和保留较少的LSC。在Bmi 1不存在的情况下，许多基因被去抑制，包括潜在的肿瘤抑制基因。移植试验表明，Bmi 1是体内白血病发展不可或缺的，Ink 4a和Arf基因的缺失只能部分恢复Bmi 1（-/-）LSC的致白血病能力。值得注意的是，永生化Bmi 1（-/-）Ink 4a-Arf（-/-）GMP与Bmi 1的互补未能恢复大多数失调基因的表达和体内致白血病活性。这些发现表明Bmi 1对于骨髓祖细胞到LSC的忠实重编程是必不可少的，并且揭示了白血病融合基因需要PcG蛋白发挥协同作用以建立LSC特异性转录谱，从而赋予LSC完整的致白血病活性。Leukemia（2011）25，1335-1343; doi：10.1038/leu.2011.85; 2011年4月29日在线发表
The polycomb group (PcG) proteins, particularly Bmi1, have an essential role in maintaining the self-renewing capacity of leukemic stem cells (LSCs). Although one of their major targets in LSCs is known to be the Ink4a/Arf tumor suppressor gene locus, the role of PcG proteins in the leukemic reprogramming of target cells into LSCs is not well characterized. In this study, Bmi1(-/-) granulocyte/macrophage progenitors (GMPs) were transformed with the leukemic fusion gene MLL-AF9. Although Bmi1 was not essential to the immortalization of GMPs in vitro, Bmi1(-/-) cells showed enhanced differentiation and retained less LSCs. A number of genes were derepressed in the absence of Bmi1 including potential tumor suppressor genes. Transplantation assays demonstrated that Bmi1 was indispensable for the development of leukemia in vivo and deletion of both the Ink4a and Arf genes only partially restored the leukemogenic capacity of Bmi1(-/-) LSCs. Of note, the complementation of immortalized Bmi1(-/-) Ink4a-Arf(-/-) GMPs with Bmi1 failed to restore the expression of the majority of deregulated genes and leukemogenic activity in vivo. These findings indicate that Bmi1 is essential for the faithful reprogramming of myeloid progenitors into LSCs and unveil that leukemic fusion genes require PcG proteins exerting an effect in concert to establish LSC-specific transcriptional profiles, which confer full leukemogenic activity on LSCs. Leukemia (2011) 25, 1335-1343; doi:10.1038/leu.2011.85; published online 29 April 2011