Bone morphogenetic proteins (BMPs) induce apoptosis and growth arrest in multiple myeloma (MM) cells.The mechanism for BMP-induced apoptosis has not been clear;however we have proposed that BMP-induced apoptosis in MM required downregulation of the oncogene c-MYC.A correlation has also been seen between induction of apoptosis and c-MYC downregulation in myeloma cells using other compounds.Deregulation of c-MYC is common in MM.Importantly, the activity of c-MYC is elevated in myeloma as compared to the premaliguant state monoclonal gammopathy of undetermined significance (MGUS), indicating a prominent role for c-MYC in myeloma pathogenesis.We wanted to further study the role of c-MYC in survival of myeloma cells.Transcriptional regulation by c-MYC requires heterodimerization of c-MYC with its obligate partner MAX.A small molecule inhibitor named 10058-F4 has been described which disrupts the formation of such heterodimers.This inhibitor was used in vitro to test the dependency on c-MYC activity in primary myeloma cells and myeloma cell lines.The inhibitor induced apoptosis in a dose-dependent manner in MM primary samples to varying degrees.Moreover, five out of six cell lines were also sensitive to 10058-F4.Using the INA-6 myeloma cell line, we found that apoptosis induced by 10058-F4 correlated with downregulation of the anti-apoptotic protein Bcl-xL.We found that apoptosis was induced by 10058-F4 even in the presence of bone marrow stromal cells derived from myeloma patients.Knowing that the specificity of small molecule inhibitors may vary, we wanted to address the potential cMYC dependency in myeloma cells using another approach.By employing RNA interference we found that repression of c-MYC by short hairpin RNA induced apoptosis in myeloma cell lines.Our results further support that c-MYC is a potential target for therapy in multiple myeloma.