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Nat Genet DOI:10.1038/ng.2777

Global chromatin profiling reveals NSD2 mutations in pediatric acute lymphoblastic leukemia.

Publication TypeJournal Article
Year of Publication2013
AuthorsJaffe, JD, Wang, Y, Chan, HMan, Zhang, J, Huether, R, Kryukov, GV, Bhang, H-eunC, Taylor, JE, Hu, M, Englund, NP, Yan, F, Wang, Z, E McDonald, R, Wei, L, Ma, J, Easton, J, Yu, Z, deBeaumount, R, Gibaja, V, Venkatesan, K, Schlegel, R, Sellers, WR, Keen, N, Liu, J, Caponigro, G, Barretina, J, Cooke, VG, Mullighan, C, Carr, SA, Downing, JR, Garraway, LA, Stegmeier, F
JournalNat Genet
Date Published2013 Nov
KeywordsAnimals, Base Sequence, Cell Line, Tumor, Child, Chromatin, Female, Genetic Predisposition to Disease, Genetic Variation, Histone-Lysine N-Methyltransferase, Histones, Humans, Mice, Mice, SCID, Neoplasm Transplantation, NIH 3T3 Cells, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Repressor Proteins, Sequence Analysis, DNA, Xenograft Model Antitumor Assays

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.


Alternate JournalNat. Genet.
PubMed ID24076604
PubMed Central IDPMC4262138
Grant List / / Howard Hughes Medical Institute / United States
P30 CA021765 / CA / NCI NIH HHS / United States
U54 CA112962 / CA / NCI NIH HHS / United States