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Nat Genet. 2014 Mar;46(3):287-93. doi: 10.1038/ng.2894. Epub 2014 Feb 9.

Identification of functional cooperative mutations of SETD2 in human acute leukemia.

Author information

1
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].
2
1] Laboratory of Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China. [2].
3
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].
4
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.
5
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.
6
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.
7
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.
8
Laboratory of Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
9
Department of Hematology, TongJi Hospital, TongJi Medical College, HuaZhong University of Science and Technology, Wuhan, Hubei, China.
10
Department of Hematology, Changhai Hospital, Second Military Medical University, Shanghai, China.
11
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.

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.

PMID:
24509477
PMCID:
PMC4440318
DOI:
10.1038/ng.2894
[Indexed for MEDLINE]
Free PMC Article

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