HoxA9 transforms murine myeloid cells by a feedback loop driving expression of key oncogenes and cell cycle control genes
HoxA9 transforms murine myeloid cells by a feedback loop driving expression of key oncogenes and cell cycle control genes
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DOI：
10.1182/bloodadvances.2018025866
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发表时间：
2018-11-27
期刊：
影响因子：
7.5
通讯作者：
Slany, Robert K.
中科院分区：
文献类型：
--
作者：
Zhong, Xiaoxia;Prinz, Andreas;Slany, Robert K.
致癌转录因子HoxA 9的异位表达是急性髓性白血病（AML）的主要原因。在这里，我们证明了HoxA 9是颗粒蛋白酶的特异性底物。蛋白酶敲除允许在原代鼠细胞和人AML细胞系中通过染色质免疫沉淀测序全面测定全基因组HoxA 9结合位点。增强子活性的动力学和转录速率响应于诱导型HoxA 9的改变进行了测定。这允许鉴定HoxA 9控制的增强子和启动子，分配到它们各自的转录单位，并区分HoxA 9结合的，但无反应的元件。HoxA 9触发了一个精心设计的正反馈回路，驱动了完整的Hox-A基因座的表达。此外，它控制关键的致癌转录因子Myc和Myb，并直接诱导细胞周期调节因子Cdk 6和CyclinD 1，以及端粒酶，绘制了通过致白血病HoxA 9表达干扰增殖的基本蓝图。
Ectopic expression of the oncogenic transcription factor HoxA9 is a major cause of acute myeloid leukemia (AML). Here, we demonstrate that HoxA9 is a specific substrate of granule proteases. Protease knockout allowed the comprehensive determination of genome-wide HoxA9 binding sites by chromatin immunoprecipitation sequencing in primary murine cells and a human AML cell line. The kinetics of enhancer activity and transcription rates in response to alterations of an inducible HoxA9 were determined. This permitted identification of HoxA9-controlled enhancers and promoters, allocation to their respective transcription units, and discrimination against HoxA9-bound, but unresponsive, elements. HoxA9 triggered an elaborate positive-feedback loop that drove expression of the complete Hox-A locus. In addition, it controlled key oncogenic transcription factors Myc and Myb and directly induced the cell cycle regulators Cdk6 and CyclinD1, as well as telomerase, drawing the essential blueprint for perturbation of proliferation by leukemogenic HoxA9 expression.