| 2 | Targeting UHRF1-SAP30-MXD4 axis for leukemia initiating cell eradication in myeloid leukemia显示文摘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. | 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 | 2022 | Cell Research2022，32，12： | 1 |
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