Abstract
Inactivation of p53 has been shown to correlate with poor prognosis and drug resistance in malignant tumors. Nevertheless, few reports have directly shown such effects in primary tumor cells. Here, we investigated the p53 mutational status in 138 B-CLL samples and compared these findings with drug and γ-irradiation sensitivity profiles. p53 mutations resulted not only in a shorter survival but, notably also in selective resistance to alkylating agents, fludarabine and γ-irradiation. In contrast, no such effect was observed for vincristine, anthracyclines and glucocorticoids. Thus, these latter compounds induce cell death at least in part by p53-independent pathways. Interestingly, p53 mutations clustered in patients who had received prior chemotherapy. In fact, we show for the first time that treatment with DNA-damaging alkylating agents correlates with occurrence of p53 mutations in a clinical setting. This finding may explain at least to some extent the development of resistance to second-line anticancer chemotherapy.
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Abbreviations
- BH:
-
Bcl-2 homology domain
- ALL:
-
acute lymphoblastic leukemia
- CLL:
-
chronic lymphocytic leukemia
- SSCP-PCR:
-
single-stranded conformational polymorphism-polymerase chain reaction
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Acknowledgements
We thank Jana Rossius, David Head, Alison Burlton and Philip Bell for expert technical assistance. The following drug companies kindly supplied drugs: Asta (mafosfamide), Schering (fludarabine). This work was funded in part by the following grants: ‘Schwerpunktprogramm Apoptose’ by the Deutsche Krebshilfe and by the network grant ‘Regulation of apoptosis in tissue homeostasis and cancer’ by the European Union ‘Training and Mobility of Researchers’ program.
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Sturm, I., Bosanquet, A., Hermann, S. et al. Mutation of p53 and consecutive selective drug resistance in B-CLL occurs as a consequence of prior DNA-damaging chemotherapy. Cell Death Differ 10, 477–484 (2003). https://doi.org/10.1038/sj.cdd.4401194
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DOI: https://doi.org/10.1038/sj.cdd.4401194
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