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Apaf1 in Chronic Myelogenous Leukemia (CML) Progression: Reduced Apaf1 Expression is Correlated with a H179R p53 Mutation During Clinical Blast Crisis
Osnat Ashur-Fabian, Konstantin Adamsky, Luba Trakhtenbrot, Yoram Cohen, Pia Raanani, Izhar Hardan, Arnon Nagler, Gideon Rechavi and Ninette Amariglio
volume 6 | issue 5
1 March 2007Pages: 589 - 594
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Chronic myelogenous leukemia (CML) is a stem cell disorder that eventually progresses to a blast crisis phase (BC) characterized by distorted apoptotic pathways. The exact mechanism leading to failure in apoptotic pathways during CML progression is unclear. In view of the central role of p53 and apaf1 in the apoptotic machinery we examined six human paired chronic and BC phases samples for their expression.
Real-time PCR (RQ-PCR) experiments showed an elevation of p53 mRNA in all patients during transition to BC. However, elevation of apaf1 during BC was observed in five patients only. In contrast, one patient displayed a significant 11.5-fold reduction of apaf1 expression during the transition to BC. No apaf1 promoter methylation was observed. The reduced apaf1 expression was accompanied by a trans-dominant point mutation (H179R) in one p53 allele and the loss of the other. This mutant p53, when tested using functionality assays, was unable to activate apaf1, consequently explaining the reduced expression observed in this patient. Furthermore, the same mutant failed to activate either genes involved in apoptotic or cell cycle arrest pathways, and can be considered as a complete loss of function mutation. This specific mutation was reported in several types of cancer, but was not implicated in CML. To conclude, in this study we have demonstrated mRNA elevation of p53 and apaf1 during CML blast crisis, indicating that genes and proteins involved in cellular apoptosis might be involved in disease progression/response to therapy. Moreover, the mutated p53 discovered in the patient exhibiting lowered apaf1 expression provides, in a clinical case, the first correlation between p53 and apaf1 transcription regulation in humans.
Authors
Osnat Ashur-Fabian
Safra Children's Hospital, Tel Aviv, Israel
Konstantin Adamsky
Safra Children's Hospital, Tel Aviv, Israel
Luba Trakhtenbrot
Safra Children's Hospital, Tel Aviv, Israel
Yoram Cohen
Safra Children's Hospital, Tel Aviv, Israel
Pia Raanani
Tel Aviv University, Tel Aviv, Israel
Izhar Hardan
Tel Aviv University, Tel Aviv, Israel
Arnon Nagler
Tel Aviv University, Tel Aviv, Israel
Gideon Rechavi
Safra Children's Hospital, Tel Aviv, Israel
Ninette Amariglio
Safra Children's Hospital, Tel Aviv, Israel
We now provide open access to journal articles published online for one year or more. This article may be downloaded at the following link:
Download PDF If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.