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 G8tract 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. Leukemia (2000) 14, 1606–1613.
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Acknowledgements
This work was supported by grants from the Deutsche Forschungsgemeinschaft (SFB 273 and SFB 506), the European Community TMR Programme. Frank Eβmann is a recipient of a fellowship from the DFG Graduiertenkolleg 331 at the University Medical Center Charité. The help of Lucia Badiali, Sabine Brühmüller, Astrid Burneleit, Wilhelm Geilen, Marianne Loewke-Wolff, Richard Schabath, Katharina Weber and Renate Wolf in the collection and preparation of samples is gratefully acknowledged. We thank Jana Roβius for her expert technical assistance.
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Prokop, A., Wieder, T., Sturm, I. et al. Relapse in childhood acute lymphoblastic leukemia is associated with a decrease of the Bax/Bcl-2 ratio and loss of spontaneous caspase-3 processing in vivo. Leukemia 14, 1606–1613 (2000). https://doi.org/10.1038/sj.leu.2401866
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DOI: https://doi.org/10.1038/sj.leu.2401866
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