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

Alok Swaroop, Jon A. Oyer, Christine M. Will, Xiaoxiao Huang, Wenbo Yu, Catalina Troche, Marinka Bulic, Benjamin H. Durham, Qiang Jeremy Wen, John D. Crispino, Alexander D. MacKerell, Richard L. Bennett, Neil L. Kelleher, Jonathan D. Licht*

*Corresponding author for this work

Research output: Contribution to journalArticle

5 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)671-686
Number of pages16
JournalOncogene
Volume38
Issue number5
DOIs
StatePublished - Jan 31 2019

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Swaroop, A., Oyer, J. A., Will, C. M., Huang, X., Yu, W., Troche, C., Bulic, M., Durham, B. H., Wen, Q. J., Crispino, J. D., MacKerell, A. D., Bennett, R. L., Kelleher, N. L., & Licht, J. D. (2019). An activating mutation of the NSD2 histone methyltransferase drives oncogenic reprogramming in acute lymphocytic leukemia. Oncogene, 38(5), 671-686. https://doi.org/10.1038/s41388-018-0474-y