An activating mutation of the NSD2 histone methyltransferase drives oncogenic reprogramming in acute lymphocytic leukemia.

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TitleAn activating mutation of the NSD2 histone methyltransferase drives oncogenic reprogramming in acute lymphocytic leukemia.
Publication TypeJournal Article
Year of Publication2018
AuthorsSwaroop, A, Oyer, JA, Will, CM, Huang, X, Yu, W, Troche, C, Bulic, M, Durham, BH, Wen, QJeremy, Crispino, JD, Mackerell, AD, Bennett, RL, Kelleher, NL, Licht, JD
JournalOncogene
Date Published2018 Aug 31
ISSN1476-5594
Abstract

NSD2, a histone methyltransferase specific for methylation of histone 3 lysine 36 (H3K36), exhibits a glutamic acid to lysine mutation at residue 1099 (E1099K) in childhood acute lymphocytic leukemia (ALL), and cells harboring this mutation can become the predominant clone in relapsing disease. We studied the effects of this mutant enzyme in silico, in vitro, and in vivo using gene edited cell lines. The E1099K mutation altered enzyme/substrate binding and enhanced the rate of H3K36 methylation. As a result, cell lines harboring E1099K exhibit increased H3K36 dimethylation and reduced H3K27 trimethylation, particularly on nucleosomes containing histone H3.1. Mutant NSD2 cells exhibit reduced apoptosis and enhanced proliferation, clonogenicity, adhesion, and migration. In mouse xenografts, mutant NSD2 cells are more lethal and brain invasive than wildtype cells. Transcriptional profiling demonstrates that mutant NSD2 aberrantly activates factors commonly associated with neural and stromal lineages in addition to signaling and adhesion genes. Identification of these pathways provides new avenues for therapeutic interventions in NSD2 dysregulated malignancies.

DOI10.1038/s41388-018-0474-y
Alternate JournalOncogene
PubMed ID30171259
Grant ListT32 CA009560 / CA / NCI NIH HHS / United States
F30 CA203292 / CA / NCI NIH HHS / United States
P41 GM108569 / GM / NIGMS NIH HHS / United States
R01 GM067193 / GM / NIGMS NIH HHS / United States
R01 CA195732 / CA / NCI NIH HHS / United States