Identification of functional cooperative mutations of SETD2 in human acute leukemia

Xiaofan Zhu; Fuhong He; Huimin Zeng; Shaoping Ling; Aili Chen; Yaqin Wang; Xiaomei Yan; Wei Wei; Yakun Pang; Hui Cheng; Chunlan Hua; Yue Zhang; Xuejing Yang; Xin Lu; Lihua Cao; Lingtong Hao; Lili Dong; Wei Zou; Jun Wu; Xia Li; Si Zheng; Jin Yan; Jing Zhou; Shuangli Mi; Xiaojuan Wang; Li Zhang; Yao Zou; Yumei Chen; Zhe Geng; Jianmin Wang; Jianfeng Zhou; Xin Liu; Jianxiang Wang; Weiping Yuan; Lixia Zhang; Gang Huang; Tao Cheng; Qian Fei Wang

doi:10.1038/ng.2894

Identification of functional cooperative mutations of SETD2 in human acute leukemia

Xiaofan Zhu, Fuhong He, Huimin Zeng, Shaoping Ling, Aili Chen, Yaqin Wang, Xiaomei Yan, Wei Wei, Yakun Pang, Hui Cheng, Chunlan Hua, Yue Zhang, Xuejing Yang, Xin Lu, Lihua Cao, Lingtong Hao, Lili Dong, Wei Zou, Jun Wu, Xia LiSi Zheng, Jin Yan, Jing Zhou, Shuangli Mi, Xiaojuan Wang, Li Zhang, Yao Zou, Yumei Chen, Zhe Geng, Jianmin Wang, Jianfeng Zhou, Xin Liu, Jianxiang Wang, Weiping Yuan, Lixia Zhang, Gang Huang, Tao Cheng, Qian Fei Wang

Research output: Contribution to journal › Article › peer-review

206 Scopus citations

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.

Original language	English (US)
Pages (from-to)	287-293
Number of pages	7
Journal	Nature Genetics
Volume	46
Issue number	3
DOIs	https://doi.org/10.1038/ng.2894
State	Published - Mar 2014
Externally published	Yes

ASJC Scopus subject areas

Genetics

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Zhu, X, He, F, Zeng, H, Ling, S, Chen, A, Wang, Y, Yan, X, Wei, W, Pang, Y, Cheng, H, Hua, C, Zhang, Y, Yang, X, Lu, X, Cao, L, Hao, L, Dong, L, Zou, W, Wu, J, Li, X, Zheng, S, Yan, J, Zhou, J, Mi, S, Wang, X, Zhang, L, Zou, Y, Chen, Y, Geng, Z, Wang, J, Zhou, J, Liu, X, Wang, J, Yuan, W, Zhang, L, Huang, G, Cheng, T & Wang, QF 2014, 'Identification of functional cooperative mutations of SETD2 in human acute leukemia', Nature Genetics, vol. 46, no. 3, pp. 287-293. https://doi.org/10.1038/ng.2894

@article{738be94b5070415cb3afd3b98a58b517,

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.",

author = "Xiaofan Zhu and Fuhong He and Huimin Zeng and Shaoping Ling and Aili Chen and Yaqin Wang and Xiaomei Yan and Wei Wei and Yakun Pang and Hui Cheng and Chunlan Hua and Yue Zhang and Xuejing Yang and Xin Lu and Lihua Cao and Lingtong Hao and Lili Dong and Wei Zou and Jun Wu and Xia Li and Si Zheng and Jin Yan and Jing Zhou and Shuangli Mi and Xiaojuan Wang and Li Zhang and Yao Zou and Yumei Chen and Zhe Geng and Jianmin Wang and Jianfeng Zhou and Xin Liu and Jianxiang Wang and Weiping Yuan and Lixia Zhang and Gang Huang and Tao Cheng and Wang, {Qian Fei}",

note = "Funding Information: 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 {\textquoteleft}Strategic Priority Research Program{\textquoteright} of the Chinese Academy of Sciences XDA01010305 (to Q.-f.W.), the {\textquoteleft}Knowledge Innovation Program{\textquoteright} 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).",

year = "2014",

month = mar,

doi = "10.1038/ng.2894",

language = "English (US)",

volume = "46",

pages = "287--293",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "3",

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TY - JOUR

T1 - Identification of functional cooperative mutations of SETD2 in human acute leukemia

AU - Zhu, Xiaofan

AU - He, Fuhong

AU - Zeng, Huimin

AU - Ling, Shaoping

AU - Chen, Aili

AU - Wang, Yaqin

AU - Yan, Xiaomei

AU - Wei, Wei

AU - Pang, Yakun

AU - Cheng, Hui

AU - Hua, Chunlan

AU - Zhang, Yue

AU - Yang, Xuejing

AU - Lu, Xin

AU - Cao, Lihua

AU - Hao, Lingtong

AU - Dong, Lili

AU - Zou, Wei

AU - Wu, Jun

AU - Li, Xia

AU - Zheng, Si

AU - Yan, Jin

AU - Zhou, Jing

AU - Mi, Shuangli

AU - Wang, Xiaojuan

AU - Zhang, Li

AU - Zou, Yao

AU - Chen, Yumei

AU - Geng, Zhe

AU - Wang, Jianmin

AU - Zhou, Jianfeng

AU - Liu, Xin

AU - Wang, Jianxiang

AU - Yuan, Weiping

AU - Zhang, Lixia

AU - Huang, Gang

AU - Cheng, Tao

AU - Wang, Qian Fei

N1 - Funding Information: 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).

PY - 2014/3

Y1 - 2014/3

N2 - 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.

AB - 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.

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U2 - 10.1038/ng.2894

DO - 10.1038/ng.2894

M3 - Article

C2 - 24509477

AN - SCOPUS:84895885401

SN - 1061-4036

VL - 46

SP - 287

EP - 293

JO - Nature Genetics

JF - Nature Genetics

IS - 3

ER -

Identification of functional cooperative mutations of SETD2 in human acute leukemia

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