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Type: Journal article
Title: Global chromatin profiling reveals NSD2 mutations in pediatric acute lymphoblastic leukemia
Author: Jaffe, J.
Wang, Y.
Chan, H.
Zhang, J.
Huether, R.
Kryukov, G.
Bhang, H.
Taylor, J.
Hu, M.
Englund, N.
Yan, F.
Wang, Z.
Mcdonald, E.
Wei, L.
Ma, J.
Easton, J.
Yu, Z.
Debeaumount, R.
Gibaja, V.
Venkatesan, K.
et al.
Citation: Nature Genetics, 2013; 45(11):1386-1393
Publisher: Nature Publishing Group
Issue Date: 2013
ISSN: 1061-4036
Statement of
Jacob D Jaffe, Yan Wang, Frank Stegmeier
Abstract: 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 Encyclopedia, 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.
Keywords: Cell Line, Tumor
Rights: © 2013, Springer Nature.
RMID: 1000003244
DOI: 10.1038/ng.2777
Appears in Collections:Medicine publications

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