Details

Autor(en) / Beteiligte

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

Titel

Identification of functional cooperative mutations of SETD2 in human acute leukemia

Ist Teil von

• Nature genetics, 2014-03, Vol.46 (3), p.287-293

Ort / Verlag

New York: Nature Publishing Group US

Erscheinungsjahr

2014

Quelle

MEDLINE

Beschreibungen/Notizen

• Tao Cheng, Qian-fei Wang, Gang Huang and colleagues identify recurrent somatic loss-of-function mutations in SETD2 in individuals with acute leukemia. SETD2 encodes a histone H3K36 methyltransferase, and loss of SETD2 function causes global loss of H3K36 trimethylation and promotes leukemia stem cell self renewal. Acute leukemia characterized by chromosomal rearrangements requires additional molecular disruptions to develop into full-blown malignancy 1 , 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 gene 3 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.