NSD2 is recruited through its PHD domain to oncogenic gene loci to drive multiple myeloma.

Histone lysine methyltransferaseNSD2 (WHSC1/MMSET) is overexpressed frequently in multiple myelomadue 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 methyltransferaseactivity is crucial for clonogenicity, adherence, and proliferation of multiple myelomacells on bone marrow stromain vitro and that NSD2 is required for tumorigenesis of t(4;14)+ but not t(4;14)− multiple myelomacells 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 myelomapatients with a t(4;14) translocation. Cancer Res; 73(20); 6277–88. ©2013 AACR .