Targeting UHRF1-SAP30-MXD4 axis for leukemia initiating cell eradication in myeloid leukemia

Author:

Hu Cheng-LongORCID,Chen Bing-Yi,Li Zijuan,Yang Tianbiao,Xu Chun-HuiORCID,Yang Ruirui,Yu Peng-Cheng,Zhao Jingyao,Liu Ting,Liu Na,Shan Bin,Zhang Qunling,Song Junhong,Fei Ming-YueORCID,Zong Li-Juan,Zhang Jia-Ying,Wu Ji-Chuan,Chen Shu-Bei,Wang Yong,Chang Binhe,Hou Dan,Liu Ping,Jiang Yilun,Li Xiya,Chen Xinchi,Deng Chu-Han,Ren Yi-Yi,Wang Roujia,Jin Jiacheng,Xue Kai,Zhang Ying,Du Meirong,Shi Jun,Wu Ling-Yun,Chang Chun-Kang,Shen Shuhong,Chen Zhu,Chen Sai-Juan,Liu XiaolongORCID,Sun Xiao-JianORCID,Zheng MingyueORCID,Wang LanORCID

Abstract

AbstractAberrant 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.

Publisher

Springer Science and Business Media LLC

Subject

Cell Biology,Molecular Biology

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