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

Autor: Swaroop A; Division of Hematology/Oncology, University of Florida Health Cancer Center, Gainesville, FL, USA.; Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA., Oyer JA; Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA., Will CM; Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA., Huang X; Division of Hematology/Oncology, University of Florida Health Cancer Center, Gainesville, FL, USA.; Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.; Department of Chemistry, Chemistry of Life Processes Institute, Northwestern University, Evanston, IL, USA.; Department of Molecular Biosciences, Chemistry of Life Processes Institute, Northwestern University, Evanston, IL, USA., Yu W; Computer-Aided Drug Design Center, Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD, USA., Troche C; Division of Hematology/Oncology, University of Florida Health Cancer Center, Gainesville, FL, USA., Bulic M; Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA., Durham BH; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Wen QJ; Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA., Crispino JD; Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA., MacKerell AD Jr; Computer-Aided Drug Design Center, Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD, USA., Bennett RL; Division of Hematology/Oncology, University of Florida Health Cancer Center, Gainesville, FL, USA., Kelleher NL; Department of Chemistry, Chemistry of Life Processes Institute, Northwestern University, Evanston, IL, USA.; Department of Molecular Biosciences, Chemistry of Life Processes Institute, Northwestern University, Evanston, IL, USA., Licht JD; Division of Hematology/Oncology, University of Florida Health Cancer Center, Gainesville, FL, USA. jdlicht@ufl.edu.; Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. jdlicht@ufl.edu.
Jazyk: angličtina
Zdroj: Oncogene [Oncogene] 2019 Jan; Vol. 38 (5), pp. 671-686. Date of Electronic Publication: 2018 Aug 31.
DOI: 10.1038/s41388-018-0474-y
Abstrakt: 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.
Databáze: MEDLINE
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