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

Authors :
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
Source :
Cell research. 32(12)
Publication Year :
2022

Abstract

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.

Details

ISSN :
17487838
Volume :
32
Issue :
12
Database :
OpenAIRE
Journal :
Cell research
Accession number :
edsair.doi.dedup.....5b9960fa5b1c2626b46b8d4386752cb8