title: NSD2 is recruited through its PHD domain to oncogenic gene loci to drive multiple myeloma.
abstract: Histone lysine methyltransferase NSD2 (WHSC1/MMSET) is overexpressed frequently in multiple myeloma due to the t(4;14) translocation associated with 15% to 20% of cases of this disease. NSD2 has been found to be involved in myelomagenesis, suggesting it may offer a novel therapeutic target. Here we show that NSD2 methyltransferase activity is crucial for clonogenicity, adherence, and proliferation of multiple myeloma cells on bone marrow stroma in vitro and that NSD2 is required for tumorigenesis of t(4;14)+ but not t(4;14)- multiple myeloma cells in vivo. The PHD domains in NSD2 were important for its cellular activity and biological function through recruiting NSD2 to its oncogenic target genes and driving their transcriptional activation. By strengthening its disease linkage and deepening insights into its mechanism of action, this study provides a strategy to therapeutically target NSD2 in multiple myeloma patients with a t(4;14) translocation.
authors: Authors' Affiliations: Novartis Institutes for BioMedical Research (China), Shanghai, P.R. China; Genomics Institute of the Novartis Research Foundation, San Diego, California; and Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
authors: Zheng
authors: Z
authors: Huang
authors: Haiping
authors: H
authors: Wu
authors: Shannon
authors: S
authors: Chuai
authors: Fiona
authors: F
authors: Xu
authors: Feng
authors: F
authors: Yan
authors: Nathan
authors: N
authors: Englund
authors: Zhaofu
authors: Z
authors: Wang
authors: Hailong
authors: H
authors: Zhang
authors: Ming
authors: M
authors: Fang
authors: Youzhen
authors: Y
authors: Wang
authors: Justin
authors: J
authors: Gu
authors: Man
authors: M
authors: Zhang
authors: Teddy
authors: T
authors: Yang
authors: Kehao
authors: K
authors: Zhao
authors: Yanyan
authors: Y
authors: Yu
authors: Jingquan
authors: J
authors: Dai
authors: Wei
authors: W
authors: Yi
authors: Shaolian
authors: S
authors: Zhou
authors: Qian
authors: Q
authors: Li
authors: Jing
authors: J
authors: Wu
authors: Jun
authors: J
authors: Liu
authors: Xu
authors: X
authors: Wu
authors: Homan
authors: H
authors: Chan
authors: Chris
authors: C
authors: Lu
authors: Peter
authors: P
authors: Atadja
authors: En
authors: E
authors: Li
authors: Yan
authors: Y
authors: Wang
authors: Min
authors: M
authors: Hu
mesh_terms: D000818:Animals; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D064593:Heterografts; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014178:Translocation, Genetic
chemical_list: D012097:Repressor Proteins; D011495:Histone-Lysine N-Methyltransferase; C419586:NSD2 protein, human