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Identification of functional cooperative mutations of SETD2 in human acute leukemia

Nature Genetics volume 46, pages 287–293 (2014)Cite this article

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Abstract

Acute leukemia characterized by chromosomal rearrangements requires additional molecular disruptions to develop into full-blown malignancy1,2, 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 gene3 and biallelic mutations in SETD2 (encoding a histone H3K36 methyltransferase)4. 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.

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Figure 1: Mutational and functional analysis of the MLL-NRIP3 fusion gene identified a monozygotic twin pair discordant for MLL-rearranged leukemia.
Figure 2: Mutational analysis of SETD2 in patients with acute leukemia.
Figure 3: H3K36me3 levels in patients with acute leukemia carrying SETD2 mutations.
Figure 4: Functional analysis of Setd2 in pre-leukemic cells.
Figure 5: Functional analysis of Setd2 in leukemic cells.

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Acknowledgements

This work was performed with the support of the Core Genomic Facility of Beijing Institute of Genomics, Chinese Academy of Sciences. We thank L. Cheng, L. Zhang, C.-I. Wu and X. Lu for their critical reading and valuable comments on the manuscript. We also thank T.R. Bartell for English editing. This study was supported by China Ministry of Science and Technology grants 2011CB964801 (to T.C.), 2012CB966600 (to W.Y. and X.Z.), 2010DFB30270 (to T.C.) and 2014CB542001 (to Q.-f.W.), National Natural Science Foundation of China grants 81090411 (to T.C.), 81130074 (to W.Y.), 30825017 (to T.C.), 81000220 (to F.H.), 81070442 (to Q.-f.W.) and 91331111 (to Q.-f.W.), the Hundred Talents Program of the Chinese Academy of Sciences (to Q.-f.W.), Tianjin Municipal Science and Technology Commission grant 09ZCZDSF03800 (to T.C.), the 'Strategic Priority Research Program' of the Chinese Academy of Sciences XDA01010305 (to Q.-f.W.), the 'Knowledge Innovation Program' of the Chinese Academy of Sciences (to F.H.) and a Pilot Research Grant of the State Key Laboratory of Experimental Hematology (to Q.-f.W. and G.H.). T.C. was a recipient of the Scholar Award from the Leukemia and Lymphoma Society (1027-08).

Author information

Author notes

  1. Xiaofan Zhu, Fuhong He, Huimin Zeng, Shaoping Ling and Aili Chen: These authors contributed equally to this work.

Authors and Affiliations

  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

    Xiaofan Zhu, Huimin Zeng, Yaqin Wang, Wei Wei, Yakun Pang, Hui Cheng, Chunlan Hua, Yue Zhang, Xiaojuan Wang, Li Zhang, Yao Zou, Yumei Chen, Jianxiang Wang, Weiping Yuan & Tao Cheng

  2. Laboratory of Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China

    Fuhong He, Shaoping Ling, Aili Chen, Xuejing Yang, Xin Lu, Lihua Cao, Lingtong Hao, Lili Dong, Wei Zou, Jun Wu, Xia Li, Si Zheng, Jin Yan, Jing Zhou, Lixia Zhang, Shuangli Mi & Qian-fei Wang

  3. Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA

    Aili Chen, Xiaomei Yan, Yue Zhang & Gang Huang

  4. Divisions of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital, Cincinnati, Ohio, USA

    Aili Chen, Xiaomei Yan, Yue Zhang & Gang Huang

  5. University of Chinese Academy of Sciences, Beijing, China

    Aili Chen, Xuejing Yang, Xin Lu, Xia Li, Si Zheng & Lixia Zhang

  6. Department of Hematology, TongJi Hospital, TongJi Medical College, HuaZhong University of Science and Technology, Wuhan, Hubei, China

    Zhe Geng & Jianfeng Zhou

  7. Department of Hematology, Changhai Hospital, Second Military Medical University, Shanghai, China

    Jianmin Wang

  8. 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

    Xin Liu

  9. Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA

    Xin Liu

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  1. Xiaofan Zhu
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  2. Fuhong He
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Contributions

X.Z. and H.Z. performed and directed clinical analyses of the study. F.H. and S.L. performed sequencing and statistical analyses and contributed to manuscript writing. A.C. performed in vitro experiments and mouse studies. Y.W., X. Yan, W.W., Y.P., H.C., C.H., Y. Zhang, X. Yang, J.Y., Jing Zhou, Lixia Zhang, S.M., X.W., Li Zhang, Y. Zou and Y.C. contributed to in vitro experiments and mouse studies. W.Y., X. Lu, X. Liu, L.C., L.H., L.D., W.Z., J. Wu, X. Li and S.Z. contributed to data analyses. Jianxiang Wang, Jianfeng Zhou, Z.G. and Jianmin Wang provided clinical samples. T.C., Q.-f.W. and G.H. conceived and directed the study and wrote the manuscript.

Corresponding authors

Correspondence to Gang Huang, Tao Cheng or Qian-fei Wang.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Note, Supplementary Figures 1–17 and Supplementary Tables 1, 2, 4–9 and 11–13 (PDF 8622 kb)

Supplementary Table 3

Clinical and Mutation information of all acute leukemia patients (XLSX 56 kb)

Supplementary Table 10

All point mutations detected using WGS data (XLSX 243 kb)

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Zhu, X., He, F., Zeng, H. et al. Identification of functional cooperative mutations of SETD2 in human acute leukemia. Nat Genet 46, 287–293 (2014). https://doi.org/10.1038/ng.2894

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