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How little is too much? p53 inactivation: from laboratory cutoff to biological basis of chemotherapy resistance

Leukemia volume 22, pages 2257–2258 (2008)Cite this article

Recent results from the UKCLL4 trial confirm the importance of determining molecular genetic markers in chronic lymphocytic leukaemia (CLL).1 Patients with 17p deletion (>20% of cells) were shown to have a complete response rate below 5% and a 100% progression rate within 3 years.1 The poor prognosis is based on the complete inactivation of the tumour suppressor p53 (deletion of one allele and mutation of the remaining allele), which is of particular importance as most current therapies rely heavily on the use of chemotherapy requiring functional p53.2 In the UKCLL4 trial, the cutoff value for 17p deletion was defined at 20%. Although it is clear that a deletion cutoff has to be defined, the hypothesis could be brought forward that more than the proportion of cells with the deletion, the status of the remaining allele may be crucial. We present two cases suggesting that 17p deletion even in a small fraction of cells is important, biologically and clinically.

In 2002, a 64-year-old patient was diagnosed with CLL (VH unmutated, ZAP70 neg., Binet B). When showing progressive disease, he was treated with FC in 2005. At this time, fluorescence in situ hybridization analysis showed a 17p deletion in 16% of the cells. After the first cycle, he developed a severe autoimmune haemolysis and the treatment was changed to rituximab plus cyclophosphamide (R-C, six cycles). He initially responded partial remission (PR), but 8 months after the termination of treatment he progressed and needed retreatment. At this time, repeat genetic analysis showed a 17p deletion in >95% of the cells. Mutational analysis of TP53 showed the same missense mutation (c.413C>T) present in both the pre- and post-therapeutic samples only at very different degrees (Figure 1b). The DHPLC profiles are shown in Figure 1B (control sample with wild-type p53 WT, the initial CLL sample prior to immunochemotherapy and at the time of refractory disease). In the pretherapeutic sample, a TP53 mutation was found in a small proportion of cells as evidenced by the very small peak (*) (p.A138V; c.413C>T). In the sample after therapy, almost all CLL cells showed the mutation. Thus, the clone with TP53 mutation was selected for during treatment with R-C. Again the cells with wild-type TP53 responded to immunochemotherapy and disappeared as evidenced by the loss of the wild-type allele (#).

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Acknowledgements

This work was supported by ‘Deutsche José Carreras Leukämie-Stiftung (R06/28v)’ and the ‘Else Kröner-Fresenius-Stiftung (P20/07//A11/07)’.

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  1. Department of Internal Medicine III, University of Ulm, Ulm, Germany

    T Zenz, S Häbe, T Denzel, D Winkler, H Döhner & S Stilgenbauer

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  1. T Zenz
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Correspondence to S Stilgenbauer.

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Zenz, T., Häbe, S., Denzel, T. et al. How little is too much? p53 inactivation: from laboratory cutoff to biological basis of chemotherapy resistance. Leukemia 22, 2257–2258 (2008). https://doi.org/10.1038/leu.2008.114

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