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

CAS Key Laboratory of Tissue Microenvironment and Tumor,Shanghai Institute of Nutrition and Health,Shanghai Institutes for Biological Sciences,University of Chinese Academy of Sciences,Chinese Academy of Sciences,Shanghai,China;State Key Laboratory of Medical Genomics,Shanghai Institute of Hematology,National Research Center for Translational Medicine,Ruijin Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai,China;Drug Discovery and Design Center,State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai,China;School of Pharmaceutical Science and Technology,Hangzhou Institute for Advanced Study,UCAS,Hangzhou,Zhejiang,China;Shanghai Institute for Advanced Immunochemical Studies,and School of Life Science and Technology,ShanghaiTech University,Shanghai,China;State Key Laboratory of Cell Biology,Chinese Academy of Sciences Center for Excellence in Molecular Cell Science,Shanghai Institute of Biochemistry and Cell Biology,Chinese Academy of Sciences,University of Chinese Academy of Sciences,Shanghai,China;Key Laboratory of Pediatric Hematology&Oncology of the Ministry of Health of China,Department of Hematology&Oncology,Shanghai Children's Medical Center,School of Medicine,Shanghai Jiao Tong University,Shanghai,China;School of Pharmacy,Fudan University,Shanghai,China;Department of lymphoma,Fudan University Shanghai Cancer Center,Shanghai,China;Department of Oncology,Shanghai Medical College,Fudan University,Shanghai,China;Shanghai Jiao Tong University School of Life Sciences and Biotechnology,Shanghai,China;Department of Hematology,Shanghai Jiao Tong University Affiliated Sixth People's Hospital,Shanghai,China;Hospital of Obstetrics and Gynecology,Fudan University Shanghai Medical College,Shanghai,China;Department of Hematology,Shanghai Ninth People's Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai,China

细胞研究（英文版）

[1]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-.Targeting UHRF1-SAP30-MXD4 axis for leukemia initiating cell eradication in myeloid leukemia)[J].细胞研究（英文版）,2022(12):1105-1123

SAP30,MXD4,methylate,Sin3A,G572,F573,derepresses,UF146

Targeting,UHRF1,axis,leukemia,initiating,eradication,myeloid,Aberrant,self,renewal,initiation,cells,LICs,drives,aggressive,acute,AML,Here,we,report,that,epigenetic,regulator,recruits,DNMT1,highly,expressed,predicts,poor,prognosis,required,leukemogenesis,by,maintaining,Mechanistically,directly,interacts,associated,protein,through,two,critical,amino,acids,SRA,domain,expression,Depletion,important,which,encodes,MYC,antagonist,leads,suppression,Further,knockdown,rescue,activating,pathway,Lastly,identified,inhibitor,demonstrated,significant,therapeutic,efficacy,PDX,model,Taken,together,our,study,reveals,mechanisms,altered,programs,provides,promising,targeted,strategy,against

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