Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
Cancer Cell. 2011 Jul 12;20(1):39-52. doi: 10.1016/j.ccr.2011.06.020.
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.
MN1 诱导的白血病中，鉴定正常细胞对致癌转化易感性的途径可能是有价值的治疗靶点。我们对 MN1 诱导的白血病中的起始细胞及其关键途径进行了特征描述。MN1 可将共同髓系祖细胞（CMP）而非粒细胞-巨噬细胞祖细胞（GMP）转化。在 GMP 中对 CMP 特征基因进行互补性研究表明，MN1 致白血病性需要 MEIS1/AbdB 样 HOX 蛋白复合物。ChIP-seq 鉴定了 MN1 和 MEIS1 的常见靶基因，并证明了它们的大量染色质靶标具有相同的结合位点。在已建立的 MN1 白血病中，MEIS1 靶基因的转录抑制作用显示出抗白血病活性。由于 MN1 依赖但不能激活 MEIS1/AbdB 样 HOX 蛋白的表达，这些基因的转录活性决定了细胞对 MN1 诱导转化的易感性，可能代表一个有前途的治疗靶点。
