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Relapse in childhood acute lymphoblastic leukemia is associated with a decrease of the Bax/Bcl-2 ratio and loss of
1Department of Pediatric Hematology/Oncology, University Medical Center Charité, Humboldt University of Berlin, Germany.
Abstract:
Dysfunction of the p53/Bax/caspase-3 apoptosis signaling pathway has been shown to play a role in tumorigenesis and tumor progression, ie the development of acquired drug resistance. Low expression of the apoptosis inducer Bax correlates with poor response to therapy and shorter overall survival in solid tumors. In the present study, we analyzed the p53/Bax/caspase-3 pathway in a paired and an unpaired sample series of children with acute lymphoblastic leukemia (ALL) at initial diagnosis and relapse. The data demonstrate that both Bax expression levels and the Bax/Bcl-2 ratio are significantly lower in samples at relapse as compared with samples at initial diagnosis (P=0.013, Wilcoxon signed rank test (paired samples); P=0.0039, Mann-Whitney U test (unpaired samples)). The loss of Bax protein expression was not a consequence of Bax frameshift mutations of the G8 tract and could not be attributed to mutations of the p53 coding sequence (exons 5 to 8) which were detected to a similar extent in de novo ALL samples and at relapse. Analysis of the downstream effector caspase-3 showed loss of spontaneous caspase-3 processing at relapse. Whereas nine out of 14 (64%, paired samples) or 37 out of 77 (48%, unpaired samples) ALL patients at initial diagnosis displayed spontaneous in vivo processing of caspase-3, this was completely absent in patients at relapse (paired samples) or detected in only one out of 34 patients at relapse (2.9%, unpaired samples). We therefore conclude that in ALL relapse a severe disturbance of apoptotic pathways occurs, both at the level of Bax expression and caspase-3 activation.
Insights
In childhood acute lymphoblastic leukemia (ALL) relapse, the apoptosis pathway is severely disturbed. Bax expression and caspase-3 activation are significantly reduced, contributing to treatment resistance.
Area of Science:
- Molecular Biology
- Oncology
- Cell Death Research
Background:
- The p53/Bax/caspase-3 apoptosis pathway is crucial in cancer development and drug resistance.
- Reduced Bax expression is linked to poor therapeutic response and survival in solid tumors.
Purpose of the Study:
- To investigate the p53/Bax/caspase-3 pathway in pediatric acute lymphoblastic leukemia (ALL) at initial diagnosis versus relapse.
- To identify molecular mechanisms underlying ALL relapse and potential therapeutic resistance.
Main Methods:
- Analysis of paired and unpaired patient samples (initial diagnosis and relapse).
- Quantification of Bax expression levels and Bax/Bcl-2 ratio.
- Mutation analysis of the Bax gene (G8 tract) and p53 coding sequence (exons 5-8).
- Assessment of spontaneous in vivo caspase-3 processing.
Main Results:
- Bax expression and Bax/Bcl-2 ratio were significantly lower in ALL relapse samples compared to initial diagnosis samples.
- Loss of Bax protein expression was not due to frameshift mutations or p53 coding sequence mutations.
- Spontaneous caspase-3 processing was absent in ALL relapse samples, contrasting with its presence at initial diagnosis.
Conclusions:
- ALL relapse is characterized by significant disturbances in apoptotic pathways, specifically reduced Bax expression and impaired caspase-3 activation.
- These apoptotic defects may contribute to the development of drug resistance and treatment failure in pediatric ALL.