Analysis of DNA from primary cancer cells has revealed large numbers of genetical aberrations, raising questions as to which mutations are “drivers” and which are “passengers”. Applying a small molecular inhibitor of MYC-MAX heterodimerization [1] we recently reported that myeloma cells treated with inhibitor rapidly undergo apoptosis [2]. Thus, a large fraction of primary myeloma cells apparently is dependent on c-MYC activity for survival.

We came to these findings by studying an entirely different aspect of myeloma cell biology, namely the mechanisms behind bone morphogenetic protein (BMP)-induced apoptosis of myeloma cells. It has been known for several years that dependent on receptor expression, various BMPs may potently induce myeloma cell death, suggesting a role for BMPs in suppressing myeloma development [3]. Analyzing the early phases of BMP-induced apoptosis in a myeloma cell line we found that the majority of genes differentially expressed between cells going to die and surviving cells also were known as transcriptional targets for c-MYC [4]. Furthermore, we could show that BMP-induced apoptosis correlated with c-MYC protein downregulation, and that c-MYC expression from a strong viral promoter protected cells from BMP-induced apoptosis. Even more interesting was a close examination of primary myeloma cells from fifteen patients where both BMP signaling and c-MYC protein status could be analyzed. Besides from expressing c-MYC protein, the cells from these patients fell into three categories; the large majority of patients (11 out of 15) had cells where BMP-induced apoptosis correlated with c-MYC downregulation. Two of the patients had cells with proper BMP-signaling but without effects on c-MYC expression levels and cell viability. These cells had translocations placing MYC under control of an immunoglobulin enhancer, thereby apparently overriding the BMP signal. The last two patients had cells with constitutive BMP signaling and no effects of added BMPs, suggesting that malignant cells from these patients had adapted to life in the presence of active BMP signaling. Taken together, the results indicate that BMP-induced apoptosis in myeloma cells is dependent on downregulation of c-MYC. However, they also suggested that if we could inhibit the activity of c-MYC in myeloma cells by other means, a majority of myeloma cell clones would not survive.