title: Identification of functional cooperative mutations of SETD2 in human acute leukemia.
abstract: Acute leukemia characterized by chromosomal rearrangements requires additional molecular disruptions to develop into full-blown malignancy, yet the cooperative mechanisms remain elusive. Using whole-genome sequencing of a pair of monozygotic twins discordant for MLL (also called KMT2A) gene-rearranged leukemia, we identified a transforming MLL-NRIP3 fusion gene and biallelic mutations in SETD2 (encoding a histone H3K36 methyltransferase). Moreover, loss-of-function point mutations in SETD2 were recurrent (6.2%) in 241 patients with acute leukemia and were associated with multiple major chromosomal aberrations. We observed a global loss of H3K36 trimethylation (H3K36me3) in leukemic blasts with mutations in SETD2. In the presence of a genetic lesion, downregulation of SETD2 contributed to both initiation and progression during leukemia development by promoting the self-renewal potential of leukemia stem cells. Therefore, our study provides compelling evidence for SETD2 as a new tumor suppressor. Disruption of the SETD2-H3K36me3 pathway is a distinct epigenetic mechanism for leukemia development.
authors: 1] State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital and Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China. [2].
authors: Xiaofan
authors: X
authors: Zhu
authors: 1] Laboratory of Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China. [2].
authors: Fuhong
authors: F
authors: He
authors: 1] State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital and Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China. [2].
authors: Huimin
authors: H
authors: Zeng
authors: 1] Laboratory of Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China. [2].
authors: Shaoping
authors: S
authors: Ling
authors: 1] Laboratory of Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China. [2] Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA. [3] Divisions of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital, Cincinnati, Ohio, USA. [4] University of Chinese Academy of Sciences, Beijing, China. [5].
authors: Aili
authors: A
authors: Chen
authors: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital and Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
authors: Yaqin
authors: Y
authors: Wang
authors: 1] Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA. [2] Divisions of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital, Cincinnati, Ohio, USA.
authors: Xiaomei
authors: X
authors: Yan
authors: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital and Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
authors: Wei
authors: W
authors: Wei
authors: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital and Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
authors: Yakun
authors: Y
authors: Pang
authors: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital and Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
authors: Hui
authors: H
authors: Cheng
authors: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital and Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
authors: Chunlan
authors: C
authors: Hua
authors: 1] State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital and Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China. [2] Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA. [3] Divisions of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital, Cincinnati, Ohio, USA.
authors: Yue
authors: Y
authors: Zhang
authors: 1] Laboratory of Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China. [2] University of Chinese Academy of Sciences, Beijing, China.
authors: Xuejing
authors: X
authors: Yang
authors: 1] Laboratory of Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China. [2] University of Chinese Academy of Sciences, Beijing, China.
authors: Xin
authors: X
authors: Lu
authors: Laboratory of Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
authors: Lihua
authors: L
authors: Cao
authors: Laboratory of Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
authors: Lingtong
authors: L
authors: Hao
authors: Laboratory of Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
authors: Lili
authors: L
authors: Dong
authors: Laboratory of Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
authors: Wei
authors: W
authors: Zou
authors: Laboratory of Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
authors: Jun
authors: J
authors: Wu
authors: 1] Laboratory of Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China. [2] University of Chinese Academy of Sciences, Beijing, China.
authors: Xia
authors: X
authors: Li
authors: 1] Laboratory of Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China. [2] University of Chinese Academy of Sciences, Beijing, China.
authors: Si
authors: S
authors: Zheng
authors: Laboratory of Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
authors: Jin
authors: J
authors: Yan
authors: Laboratory of Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
authors: Jing
authors: J
authors: Zhou
authors: 1] Laboratory of Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China. [2] University of Chinese Academy of Sciences, Beijing, China.
authors: Lixia
authors: L
authors: Zhang
authors: Laboratory of Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
authors: Shuangli
authors: S
authors: Mi
authors: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital and Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
authors: Xiaojuan
authors: X
authors: Wang
authors: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital and Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
authors: Li
authors: L
authors: Zhang
authors: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital and Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
authors: Yao
authors: Y
authors: Zou
authors: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital and Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
authors: Yumei
authors: Y
authors: Chen
authors: Department of Hematology, TongJi Hospital, TongJi Medical College, HuaZhong University of Science and Technology, Wuhan, Hubei, China.
authors: Zhe
authors: Z
authors: Geng
authors: Department of Hematology, Changhai Hospital, Second Military Medical University, Shanghai, China.
authors: Jianmin
authors: J
authors: Wang
authors: Department of Hematology, TongJi Hospital, TongJi Medical College, HuaZhong University of Science and Technology, Wuhan, Hubei, China.
authors: Jianfeng
authors: J
authors: Zhou
authors: 1] Mary Ann and J. Milburn Smith Child Health Research Program, Ann and Robert H. Lurie Children's Hospital of Chicago Research Center, Chicago, Illinois, USA. [2] Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors: Xin
authors: X
authors: Liu
authors: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital and Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
authors: Jianxiang
authors: J
authors: Wang
authors: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital and Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
authors: Weiping
authors: W
authors: Yuan
authors: 1] Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA. [2] Divisions of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital, Cincinnati, Ohio, USA.
authors: Gang
authors: G
authors: Huang
authors: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital and Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
authors: Tao
authors: T
authors: Cheng
authors: Laboratory of Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
authors: Qian-Fei
authors: QF
authors: Wang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D002675:Child, Preschool; D002869:Chromosome Aberrations; D004200:Diseases in Twins / Q000235:genetics; D044127:Epigenesis, Genetic; D005260:Female; D050939:Gene Fusion; D016147:Genes, Tumor Suppressor; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006801:Humans; D007938:Leukemia / Q000235:genetics*; D007948:Leukemia, Monocytic, Acute / Q000235:genetics; D009154:Mutation; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D017354:Point Mutation; D014178:Translocation, Genetic; D014430:Twins, Monozygotic
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C501825:DCAF6 protein, human; C497422:KMT2A protein, human; D009687:Nuclear Proteins; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C521636:SETD2 protein, human