基本螺旋-环-螺旋转录因子 SHARP1 是 MLL-AF6 急性髓系白血病的致癌驱动因子。
The basic helix-loop-helix transcription factor SHARP1 is an oncogenic driver in MLL-AF6 acute myelogenous leukemia.
机构信息
Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore.
MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, NIHR Oxford Biomedical Research Centre Programme, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DS, UK.
出版信息
Nat Commun. 2018 Apr 24;9(1):1622. doi: 10.1038/s41467-018-03854-0.
Acute Myeloid Leukemia (AML) with MLL gene rearrangements demonstrate unique gene expression profiles driven by MLL-fusion proteins. Here, we identify the circadian clock transcription factor SHARP1 as a novel oncogenic target in MLL-AF6 AML, which has the worst prognosis among all subtypes of MLL-rearranged AMLs. SHARP1 is expressed solely in MLL-AF6 AML, and its expression is regulated directly by MLL-AF6/DOT1L. Suppression of SHARP1 induces robust apoptosis of human MLL-AF6 AML cells. Genetic deletion in mice delays the development of leukemia and attenuated leukemia-initiating potential, while sparing normal hematopoiesis. Mechanistically, SHARP1 binds to transcriptionally active chromatin across the genome and activates genes critical for cell survival as well as key oncogenic targets of MLL-AF6. Our findings demonstrate the unique oncogenic role for SHARP1 in MLL-AF6 AML.
急性髓系白血病（AML）伴 MLL 基因重排表现出独特的基因表达谱，由 MLL 融合蛋白驱动。在这里，我们确定昼夜节律转录因子 SHARP1 是 MLL-AF6 AML 中的一个新的致癌靶点，在所有 MLL 重排 AML 亚型中，其预后最差。SHARP1 仅在 MLL-AF6 AML 中表达，其表达受 MLL-AF6/DOT1L 的直接调控。抑制 SHARP1 可诱导人 MLL-AF6 AML 细胞发生强烈的凋亡。在小鼠中进行基因缺失可延迟白血病的发展并减弱白血病起始潜能，同时不影响正常造血。从机制上讲，SHARP1 结合到基因组上转录活跃的染色质上，并激活对细胞存活至关重要的基因以及 MLL-AF6 的关键致癌靶点。我们的研究结果表明 SHARP1 在 MLL-AF6 AML 中具有独特的致癌作用。
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