This considerable heterogeneity was an obstacle to our pooled analysis of study results

ein partners are unknown, but a varying recruitment of p210BCR-ABL to the centrosome may conceivable. The observed hyperactivation of Separase in b3a2 cells correlates with our cytogenetic data and points to higher “escape skills” of b3a2 leukemic stem cells that obviously outperform b2a2 cells in terms of unbalanced ACA acquisition and clonal evolution. The increased potential for clonal PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19704093 evolution and development of resistance may help b3a2 progenitors to escape the immunological and therapeutic pressure in terms of the Darwinian tumor model. This assumption is concordant with the pathology of CML: Development of resistance in patients undergoing IM therapy frequently concurs with clonal evolution, which points to clonal evolution as a mechanism of resistance. Furthermore, under IM the outcome of patients with clonal evolution is significantly inferior compared to those without. 13 / 18 Separase Activity in CML It is therefore tempting to speculate that the IM-related hyperactivation of Separase proteolytic activity exclusively in b3a2 bcr-abl-positive cells is the best candidate mechanism for explaining promotion of tumor heterogeneity and clonal evolution. Even in dormant p210BCR-ABL low-expressing quiescent stem cells, this mechanism may eventually create descendant cell populations with enhanced fidelity to escape therapeutic pressure. This suits the general opinion that newly arising ACA under treatment are a clear sign of therapy failure. Our data seem to contradict the general opinion that b3a2 patients show better molecular responses than b2a2 patients. However, no difference in cytogenetic response and overall survival has been previously reported when comparing the impact of b3a2 and b2a2 splice variants on disease phenotype and outcome under imatinib therapy. Therefore, we conclude that our proposed Separase-related mechanism favoring specifically the acquisition of unbalanced ACA in b3a2 patients has no detectable influence on clinical response and overall survival. However, our clinical results clearly demonstrate that there are differences between b2a2 and b3a2 patients during IM treatment in terms of ACA type and PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19704080 time to blast crisis. These differences seem to be clinically relevant. Because of the rather small sample size and the relatively low number of statistical tests performed we refrained from Bonferroni correction in order to control the overall type I error rate. Otherwise, differences between both groups may have been missed. However, even if the p value is multiplicated by 4 the difference regarding “time to BC” remains statistically significant whereas the difference regarding the p210BCR-ABL splice variant shows a trend. In conclusion, our data indicate the existence of a p210BCR-ABL-related feedback mechanism that posttranslationally stimulates Separase proteolytic activity after an IM-induced decrease in Separase protein levels exclusively in b3a2 fusion type CML cells. As a consequence, b3a2 cells may be more susceptible to chromosomal missegregation and clonal evolution than leukemic b2a2 progenitors. Prospective studies on the Separase regulatory network in CML may give rise to new concepts in carcinogenesis and leukemia therapy using selective Separase inhibitors. ~~ Atherosclerotic vascular diseases are the leading cause of death globally. Although there are numerous well-established factors that increase risk for ASVD, including genetic factors, hypertension, Aphrodine hypercholesterolemia and smoking, these d