The multiple myeloma associated MMSET gene contributes to cellular adhesion, clonogenic growth, and tumorigenicity.
Multiple myeloma (MM) is an incurable hematologic malignancy characterized by recurrent chromosomal translocations. Patients with t(4;14)(p16;q32) are the worst prognostic subgroup in MM, although the basis for this poor prognosis is unknown. The t(4;14) is unusual in that it involves 2 potential target genes: fibroblast growth factor receptor 3 (FGFR3) and multiple myeloma SET domain (MMSET). MMSET is universally overexpressed in t(4;14) MM, whereas FGFR3 expression is lost in one-third of cases. Nonetheless, the role of MMSET in t(4;14) MM has remained unclear. Here we demonstrate a role for MMSET in t(4;14) MM cells. Down-regulation of MMSET expression in MM cell lines by RNA interference and by selective disruption of the translocated MMSET allele using gene targeting dramatically reduced colony formation in methylcellulose but had only modest effects in liquid culture. In addition, MMSET knockdown led to cell-cycle arrest of adherent MM cells and reduced the ability of MM cells to adhere to extracellular matrix. Finally, MMSET knockdown and knockout reduced tumor formation by MM xenografts. These results provide the first direct evidence that MMSET plays a significant role in t(4;14) MM and suggest that therapies targeting this gene could impact this particular subset of poor-prognosis patients.
Lauring
Josh
J
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Department of Chemical and Biomolecular Engineering, Baltimore, MD 21231, USA. jlaurin1@jhmi.edu
Abukhdeir
Abde M
AM
Konishi
Hiroyuki
H
Garay
Joseph P
JP
Gustin
John P
JP
Wang
Qiuju
Q
Arceci
Robert J
RJ
Matsui
William
W
Park
Ben Ho
BH
D000483:Alleles; D000818:Animals; D002448:Cell Adhesion / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics / Q000378:metabolism; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics / Q000378:metabolism; D003114:Colony-Forming Units Assay; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D018390:Gene Targeting; D011495:Histone-Lysine N-Methyltransferase / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009101:Multiple Myeloma / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D009368:Neoplasm Transplantation; D011379:Prognosis; D034622:RNA Interference; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000096:biosynthesis / Q000235:genetics; D012097:Repressor Proteins / Q000096:biosynthesis* / Q000235:genetics; D014178:Translocation, Genetic / Q000235:genetics; D014183:Transplantation, Heterologous
D012097:Repressor Proteins; D011495:Histone-Lysine N-Methyltransferase; C419586:NSD2 protein, human; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3