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 journalArticlepeer-review

182 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 languageEnglish (US)
Pages (from-to)287-293
Number of pages7
JournalNature Genetics
Volume46
Issue number3
DOIs
StatePublished - Mar 2014
Externally publishedYes

ASJC Scopus subject areas

  • Genetics

Fingerprint

Dive into the research topics of 'Identification of functional cooperative mutations of SETD2 in human acute leukemia'. Together they form a unique fingerprint.

Cite this