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

Oncogene
Alok SwaroopJ D Licht

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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Citations

May 31, 2019·Cellular and Molecular Life Sciences : CMLS·Jie LiGang Greg Wang
Sep 11, 2019·International Journal of Molecular Sciences·Pavel Klener
May 17, 2019·Indian Journal of Clinical Biochemistry : IJCB·Aman KumarRajendra Prasad
Jan 27, 2021·Cancers·Timon A BloedjesJeroen E J Guikema
Dec 11, 2020·Nature·Nevin YusufovaAri M Melnick
Nov 5, 2020·Pharmacology & Therapeutics·Elena KunadisChristina Piperi
May 19, 2021·Nature Reviews. Cancer·Shuai ZhaoGang Greg Wang

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Datasets Mentioned

BETA
SRP135822

Methods Mentioned

BETA
pulldown
fluorescence recovery after photobleaching
Assay
flow cytometry
xenograft
RNA-seq
Transfection
Co-IP
PCR

Software Mentioned

SWISS
REDUCE
GraphPad
MODEL
Enrichr GSEA
ZDOCK
GSEA
RSEM
Trimmomatic
STAR

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