Apaf1 in chronic myelogenous leukemia (CML) progression: reduced Apaf1 expression is correlated with a H179R p53 mutation during clinical blast crisis.

Chronic myelogenous leukemia (CML) is a stem cell disorder that eventually progresses to ablast crisis phase (BC) characterized by distorted apoptotic pathways. The exact mechanismleading to failure in apoptotic pathways during CML progression is unclear. In view of thecentral role of p53 and apaf1 in the apoptotic machinery we examined six human pairedchronic and BC phases samples for their expression.Real-time PCR (RQ-PCR) experiments showed an elevation of p53 mRNA in all patientsduring transition to BC. However, elevation of apaf1 during BC was observed in five patientsonly. In contrast, one patient displayed a significant 11.5-fold reduction of apaf1 expressionduring the transition to BC. No apaf1 promoter methylation was observed. The reduced apaf1expression was accompanied by a trans-dominant point mutation (H179R) in one p53 alleleand the loss of the other. This mutant p53, when tested using functionality assays, was unableto activate apaf1, consequently explaining the reduced expression observed ...