Portal de Periódicos da CAPES

Global chromatin profiling reveals NSD2 mutations in pediatric acute lymphoblastic leukemia

2013; Nature Portfolio; Volume: 45; Issue: 11 Linguagem: Inglês

10.1038/ng.2777

1546-1718

Jacob D. Jaffe, Yan Wang, Ho Man Chan, Jinghui Zhang, Robert Huether, Gregory V. Kryukov, Hyo-Eun Carrie Bhang, Jordan E. Taylor, Min Hu, Nathan Englund, Feng Yan, Zhaofu Wang, E. Robert McDonald, Lei Wei, Jing Ma, John Easton, Zhengtian Yu, Rosalie deBeaumount, Veronica Gibaja, K. Venkatesan, Robert Schlegel, William R. Sellers, Nicholas Keen, Jun Liu, Giordano Caponigro, Jordi Barretina, Vesselina G. Cooke, Charles G. Mullighan, Steven A. Carr, James R. Downing, Levi A. Garraway, Frank Stegmeier,

Childhood Cancer Survivors' Quality of Life

Frank Stegmeier, Levi Garraway and colleagues apply a targeted mass spectrometry approach that measures level of histone modifications and identify a recurrent p.E1099K variant in NSD2 in acute lymphoblastic leukemia. When ectopically expressed in a cancer cell line, this variant promotes transformation. 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 NSD2-mutant lines and impaired the in vivo growth of an NSD2-mutant 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.