Down-Regulation of MMSET by RNA Interference Affects Cell Viability and Tumorigenicity in t(4;14) Myeloma Plasma Cells

Abstract 3998

The recurrent immunoglobulin translocation, t(4;14)(p16;q32) occurs in 15% of multiple myeloma patients and is 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 involvement of MMSET in the pathogenesis of t(4;14) multiple myeloma and the mechanism or genes deregulated by MMSET upregulation are still unclear. Here we demonstrate a role for MMSET in t(4;14) MM cells. We found that Down-regulation of MMSET expression in KMS11 cell by RNA interference and by selective disruption of the translocated MMSET allele using gene targeting dramatically reduced DNA synthesis in KMS11 decreased to 20% of that of the control, whereas the viability of cells decreased to 2% (p_ 0.01) of that of the control and increase in apoptosis was twice that of the control. These findings were associated with reduced expression of genes (e.g. CCND2, CCNG1, MAF and VEGF). These results provide direct evidence that MMSET plays a significant cell survival and antiapoptotic role in t(4;14) MM and suggest that therapies targeting this gene could impact this particular subset of poor-prognosis patients.