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

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.

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Authors contribution

A.S., J.A.O., C.M.W., X.H., W.Y., R.L.B., N.L.K., and J.D.L. designed and analyzed experiments. A.S., J.A.O., C.M.W., X.H., W.Y., R.L.B., C.T., M.B., Q.W.J., and B.H.D. performed experiments. A.S., J.D.L., and R.L.B. prepared the manuscript. J.D.C., A.D.M., and N.L.K. provided conceptual and technical advice.

Funding

Supported by T32 CA009560 (AS), F30 CA203292 (AS), R01 CA195732 (JDL), R01 GM051501 (ADM), a Leukemia and Lymphoma Society Specialized Center of Excellence grant (JDL), the Samuel Waxman Cancer Research Foundation (ADM and JDL) and Celgene (JDL), P41 GM108569 and R01 GM067193 (NLK) and the Lauri Strauss Leukemia Foundation (JAO, CT).

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Correspondence to Jonathan D. Licht.

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Swaroop, A., Oyer, J.A., Will, C.M. et al. An activating mutation of the NSD2 histone methyltransferase drives oncogenic reprogramming in acute lymphocytic leukemia. Oncogene 38, 671–686 (2019). https://doi.org/10.1038/s41388-018-0474-y

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