Global chromatin profiling reveals NSD2 mutations in pediatric acute lymphoblastic leukemia

作者：Jaffe Jacob D; Wang Yan; Chan Ho Man; Zhang Jinghui; Huether Robert; Kryukov Gregory V; Bhang Hyo eun C; Taylor Jordan E; Hu Min; Englund Nathan P; Yan Feng; Wang Zhaofu; McDonald E Robert III; Wei Lei; Ma Jing; Easton John; Yu Zhengtian; deBeaumount Rosalie; Gibaja Veronica; Venkatesan Kavitha; Schlegel Robert; Sellers William R; Keen Nicholas; Liu Jun; Caponigro Giordano; Barretina Jordi; Cooke Vesselina G; Mullighan Charles; Carr Steven A

来源：Nature Genetics, 2013, 45(11): 1386-+.

DOI：10.1038/ng.2777

Epigenetic dysregulation is an emerging hallmark of cancers. We developed a high-information-content mass spectrometry approach to profile global histone modifications in human cancers. When applied to 115 lines from the Cancer Cell Line Encyclopedia1, this approach identified distinct molecular chromatin signatures. One signature was characterized by increased histone 3 lysine 36 (H3K36) dimethylation, exhibited by several lines harboring translocations in NSD2, which encodes a methyltransferase. A previously unknown NSD2 p. Glu1099Lys (p. E1099K) variant was identified in nontranslocated acute lymphoblastic leukemia (ALL) cell lines sharing this signature. Ectopic expression of the variant induced a chromatin signature characteristic of NSD2 hyperactivation and promoted transformation. NSD2 knockdown selectively inhibited the proliferation of NSD2mutant lines and impaired the in vivo growth of an NSD2mutant ALL xenograft. Sequencing analysis of > 1,000 pediatric cancer genomes identified the NSD2 p. E1099K alteration in 14% of t (12; 21) ETV6-RUNX1-containing ALLs. These findings identify NSD2 as a potential therapeutic target for pediatric ALL and provide a general framework for the functional annotation of cancer epigenomes.

• 出版日期2013-11