在髓系白血病中以UHRF1-SAP30-MXD4轴为目标，以清除造血干细胞。
Targeting UHRF1-SAP30-MXD4 axis for leukemia initiating cell eradication in myeloid leukemia.
发表日期：2022 Dec
作者：
Cheng-Long Hu, Bing-Yi Chen, Zijuan Li, Tianbiao Yang, Chun-Hui Xu, Ruirui Yang, Peng-Cheng Yu, Jingyao Zhao, Ting Liu, Na Liu, Bin Shan, Qunling Zhang, Junhong Song, Ming-Yue Fei, Li-Juan Zong, Jia-Ying Zhang, Ji-Chuan Wu, Shu-Bei Chen, Yong Wang, Binhe Chang, Dan Hou, Ping Liu, Yilun Jiang, Xiya Li, Xinchi Chen, Chu-Han Deng, Yi-Yi Ren, Roujia Wang, Jiacheng Jin, Kai Xue, Ying Zhang, Meirong Du, Jun Shi, Ling-Yun Wu, Chun-Kang Chang, Shuhong Shen, Zhu Chen, Sai-Juan Chen, Xiaolong Liu, Xiao-Jian Sun, Mingyue Zheng, Lan Wang
来源：
CELL RESEARCH
摘要：
白血病干细胞（LICs）的异常自我更新驱动侵袭性急性髓系白血病（AML）。我们报道了一个表观遗传调节器UHRF1在AML中高度表达，并预示着不良预后。UHRF1通过维护LICs的自我更新来促进髓样白血病发生。机械上，UHRF1通过其SRA结构域中的两个关键氨基酸G572和F573与Sin3A相关蛋白30（SAP30）直接相互作用，以抑制基因表达。UHRF1或SAP30的耗竭使一个重要的靶基因MXD4解除沉默，该基因编码MYC拮抗剂，并导致白血病发生的抑制。进一步敲低MXD4可以通过激活MYC通路来挽救白血病发生。最后，我们确定一种UHRF1抑制剂UF146，并证明其在髓性白血病PDX模型中具有显著的治疗功效。综上所述，我们的研究揭示了AML中改变表观遗传程序的机制，并提供了一种有前途的针对AML的靶向治疗策略。©2022年作者（们）。
Aberrant self-renewal of leukemia initiation cells (LICs) drives aggressive acute myeloid leukemia (AML). Here, we report that UHRF1, an epigenetic regulator that recruits DNMT1 to methylate DNA, is highly expressed in AML and predicts poor prognosis. UHRF1 is required for myeloid leukemogenesis by maintaining self-renewal of LICs. Mechanistically, UHRF1 directly interacts with Sin3A-associated protein 30 (SAP30) through two critical amino acids, G572 and F573 in its SRA domain, to repress gene expression. Depletion of UHRF1 or SAP30 derepresses an important target gene, MXD4, which encodes a MYC antagonist, and leads to suppression of leukemogenesis. Further knockdown of MXD4 can rescue the leukemogenesis by activating the MYC pathway. Lastly, we identified a UHRF1 inhibitor, UF146, and demonstrated its significant therapeutic efficacy in the myeloid leukemia PDX model. Taken together, our study reveals the mechanisms for altered epigenetic programs in AML and provides a promising targeted therapeutic strategy against AML.© 2022. The Author(s).