机构：[1]Divisions of Pathology and Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA[2]Laboratory of Vaccine and Antibody Engineering, Beijing Institute of Biotechnology, 20 Dongdajie Street, Fengtai District, Beijing 100071, People’s Republic of China[3]CAS Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China[4]State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China[5]Key Laboratory of Regenerative Medicine of Ministry of Education, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou 510632, China[6]Institute of Aging Research, Hangzhou Normal University School of Medicine, Hangzhou 310003, China[7]Present address: Henan University of Chinese Medicine, Zhengzhou, Henan 450046, China
SETD2, an epigenetic tumor suppressor, is frequently mutated in MLL-rearranged (MLLr) leukemia and relapsed acute leukemia (AL). To clarify the impact of SETD2 mutations on chemotherapy sensitivity in MLLr leukemia, two loss-of-function (LOF) Setd2-mutant alleles (Setd2F2478L/WT or Setd2Ex6-KO/WT) were generated and introduced, respectively, to the Mll-Af9 knock-in leukemia mouse model. Both alleles cooperated with Mll-Af9 to accelerate leukemia development that resulted in resistance to standard Cytarabine-based chemotherapy. Mechanistically, Setd2-mutant leukemic cells showed downregulated signaling related to cell cycle progression, S, and G2/M checkpoint regulation. Thus, after Cytarabine treatment, Setd2-mutant leukemic cells exit from the S phase and progress to the G2/M phase. Importantly, S and G2/M cell cycle checkpoint inhibition could resensitize the Mll-Af9/Setd2 double-mutant cells to standard chemotherapy by causing DNA replication collapse, mitotic catastrophe, and increased cell death. These findings demonstrate that LOF SETD2 mutations confer chemoresistance on AL to DNA-damaging treatment by S and G2/M checkpoint defects. The combination of S and G2/M checkpoint inhibition with chemotherapy can be explored as a promising therapeutic strategy by exploiting their unique vulnerability and resensitizing chemoresistant AL with SETD2 or SETD2-like epigenetic mutations.
基金：
Cincinnati Children’s
Hospital Research Foundation (to P.R.A. and to G.H.), the
Leukemia Research Foundation (to G.H.), the OCRA (to G.H.), the CFK
(to G.H.), National Institutes of Health (NIH) (R21CA187276 to G.H.),
the National Natural Science Foundation of China (NSFC) (grant
81470297 and grant 81770129 to G.H., and grant 81471911 to X.Z.),
and the “Personalized Medicines–Molecular Signature-based Drug
Discovery and Development”, Strategic Priority Research Program of
the Chinese Academy of Sciences (grant XDA12020362 to Q.-f. Wang).
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2018]版：
大类|1 区医学
小类|1 区血液学1 区肿瘤学
最新[2025]版：
大类|1 区医学
小类|1 区血液学2 区肿瘤学
第一作者：
第一作者机构：[1]Divisions of Pathology and Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA[2]Laboratory of Vaccine and Antibody Engineering, Beijing Institute of Biotechnology, 20 Dongdajie Street, Fengtai District, Beijing 100071, People’s Republic of China
共同第一作者：
通讯作者：
通讯机构：[1]Divisions of Pathology and Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA[4]State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
推荐引用方式(GB/T 7714)：
Dong Yunzhu,Zhao Xinghui,Feng Xiaomin,et al.SETD2 mutations confer chemoresistance in acute myeloid leukemia partly through altered cell cycle checkpoints.[J].Leukemia.2019,33(11):2585-2598.doi:10.1038/s41375-019-0456-2.
APA：
Dong Yunzhu,Zhao Xinghui,Feng Xiaomin,Zhou Yile,Yan Xiaomei...&Huang Gang.(2019).SETD2 mutations confer chemoresistance in acute myeloid leukemia partly through altered cell cycle checkpoints..Leukemia,33,(11)
MLA：
Dong Yunzhu,et al."SETD2 mutations confer chemoresistance in acute myeloid leukemia partly through altered cell cycle checkpoints.".Leukemia 33..11(2019):2585-2598
医学