Cell of Origin in AML: Susceptibility to MN1-Induced Transformation Is Regulated by the MEIS1/AbdB-like HOX Protein Complex
Cell of Origin in AML: Susceptibility to MN1-Induced Transformation Is Regulated by the MEIS1/AbdB-like HOX Protein Complex
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DOI：
10.1016/j.ccr.2011.06.020
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发表时间：
2011-07-12
期刊：
影响因子：
50.3
通讯作者：
Humphries, R. Keith
中科院分区：
文献类型：
--
作者：
Heuser, Michael;Yun, Haiyang;Humphries, R. Keith
定义正常细胞对致癌转化的易感性的途径可能是有价值的治疗靶点。我们描述了MN 1诱导的白血病的起源细胞及其关键途径。MN 1可转化普通髓系祖细胞（CMP），但不能转化粒细胞-巨噬细胞祖细胞（GMP）。GMP中CMP标记基因的互补研究表明，MN 1致白血病需要MEIS 1/AbdB样HOX蛋白复合物。ChIP测序鉴定了MN 1和MEIS 1的共同靶基因，并证明了它们的大部分染色质靶点具有相同的结合位点。在已建立的MN 1白血病中MEIS 1靶点的转录抑制表现出抗白血病活性。由于MN 1依赖于但不能激活MEIS 1/AbdB样HOX蛋白的表达，这些基因的转录活性决定了细胞对MN 1诱导的转化的易感性，并可能代表一个有前途的治疗靶点。
Pathways defining susceptibility of normal cells to oncogenic transformation may be valuable therapeutic targets. We characterized the cell of origin and its critical pathways in MN1-induced leukemias. Common myeloid (CMP) but not granulocyte-macrophage progenitors (GMP) could be transformed by MN1. Complementation studies of CMP-signature genes in GMPs demonstrated that MN1-leukemogenicity required the MEIS1/AbdB-like HOX-protein complex. ChIP-sequencing identified common target genes of MN1 and MEIS1 and demonstrated identical binding sites for a large proportion of their chromatin targets. Transcriptional repression of MEIS1 targets in established MN1 leukemias demonstrated antileukemic activity. As MN1 relies on but cannot activate expression of MEIS1/AbdB-like HOX proteins, transcriptional activity of these genes determines cellular susceptibility to MN1-induced transformation and may represent a promising therapeutic target.