Oncogene addiction to c-MYC in myeloma cells.

摘要: Analysis of DNA from primary cancer cells has revealed large numbers genetical aberrations, raising questions as to which mutations are “drivers” and “passengers”. Applying a small molecular inhibitor MYC-MAX heterodimerization [1] we recently reported that myeloma treated with rapidly undergo apoptosis [2]. Thus, fraction apparently is dependent on c-MYC activity for survival. We came these findings by studying an entirely different aspect cell biology, namely the mechanisms behind bone morphogenetic protein (BMP)-induced cells. It been known several years receptor expression, various BMPs may potently induce death, suggesting role in suppressing development [3]. Analyzing early phases BMP-induced line found majority genes differentially expressed between going die surviving also were transcriptional targets [4]. Furthermore, could show correlated downregulation, expression strong viral promoter protected apoptosis. Even more interesting was close examination fifteen patients where both BMP signaling status be analyzed. Besides expressing protein, fell into three categories; (11 out 15) had downregulation. Two proper BMP-signaling but without effects levels viability. These translocations placing MYC under control immunoglobulin enhancer, thereby overriding signal. The last two constitutive no added BMPs, malignant adapted life presence active signaling. Taken together, results indicate downregulation c-MYC. However, they suggested if inhibit other means, clones would not survive. A earlier gene studies indicating signature detected approximately 70% contrast pre-malignant condition, monoclonal gammopathy undetermined significance (MGUS) [5]. shown important survival lines because RNA interference induces some [6]. major difference latter proliferate very slowly, implicated proliferation, it obvious what cells. Based this went study applying heterodimerization; 10058-F4 compound. Treatment led induction clones, survival. Genetic rearrangements affecting considered late events common derived stage plasmacytomas [7]. As analyzed our obtained newly diagnosed, untreated patients, suggest deregulation relatively event course multiple myeloma. The raises questions. First all, specificity pharmacological inhibitors always matter concern. Moreover, compound represents new class does enzyme rather bi-molecular interaction its partner MAX. did affect U266 even at high concentrations, clearly independent express Secondly, vitro relevant vivo. On hand killed marrow stromal mimic aspects microenvironment. Despite significant advances treatment during couple decades, remains incurable better therapies needed. efficacy inhibition therapy remains, however, determined. Unfortunately, applicable vivo due rapid degradation [8], so drugs there great hope approach animal experiments have lymphomas recurring after suppression continued exhibit oncogene addiction [9]. many cases central functional nonredundancy, easily replaced alternative [10].