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Blood, 15 January 2008, Vol. 111, No. 2, pp. 856-864.
Prepublished online as a Blood First Edition Paper on October 17, 2007; DOI 10.1182/blood-2007-05-088674.
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Submitted May 3, 2007
Accepted October 10, 2007
The multiple myeloma-associated MMSET gene contributes to cellular adhesion, clonogenic growth, and tumorigenicity
Josh Lauring*, Abde M. Abukhdeir, Hiroyuki Konishi, Joseph P. Garay, John P. Gustin, Qiuju Wang, Robert J. Arceci, William Matsui, and Ben Ho Park
Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, United States
Department of Chemical and Biomolecular Engineering, The Whiting School of Engineering, The Johns Hopkins University, Baltimore, MD, United States
* Corresponding author; email: jlaurin1{at}jhmi.edu.
Multiple myeloma (MM) is an incurable hematological 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 two potential target genes: fibroblast growth factor receptor 3 (FGFR3) and multiple myeloma SET domain (MMSET). MMSET is universally over-expressed 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 (RNAi) 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. Additionally, 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.
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