MDM2 PROTEIN OVEREXPRESSION PROMOTES PROLIFERATION AND SURVIVAL OF MULTIPLE-MYELOMA CELLS

The murine double minute 2 (MDM2) protein facilitates G1 to S phase tr ansition by activation of E2F-1 and can enhance cell survival by suppr essing wild-type p53 (wtp53) function. In this study, we examined MDM2 expression and function in multiple myeloma (MM) cells, MDM2 is stron gly and constitutively expressed in MM cell lines (ARH-77, RPMI 8226, and OCl-My5) and in the cells of plasma cell leukemia (PCL) patients, but is not expressed in normal bone marrow mononuclear cells (BM MNCs) . Treatment of MM cells with MDM2 antisense, but not sense, nonsense, or scrambled, oligodeoxyribonucleotides (ODNs) decreased DNA synthesis and cell viability; it also induced G1 growth arrest, as evidenced by propidium iodide (pi) staining and induction of retinoblastoma protei n (pRB) to E2F-1 binding. Moreover, inhibition of MDM2 using antisense ODNs also triggered MM cell apoptosis as evidenced by acridine orange -ethidium bromide staining. We next studied the association of MDM2 wi th wtp53 and/or mutant p53 (mtp53), E2f-1, CDK4, and p21. MDM2 constit utively hinds to E2F-1 in all MM cells, to both wtp53 and mtp53, and t o p21 in tumor cells lacking p53. These data suggest that MDM2 may enh ance cell-cycle progression in NIM cells both by activating E2F-1 and by downregulating cell-cycle inhibitory proteins (wtp53 and p21), Over expression of MDM2 may therefore contribute to both growth and surviva l of MM cells, suggesting the potential utility of treatment strategie s targeting MDM2 in MM. (C) 1997 by nle American Society of Hematology .