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The expression levels of the pro-apoptotic XAF-1 gene modulate the cytotoxic response to Nutlin-3 in B chronic lymphocytic leukemia

Leukemia volume 24, pages 480–483 (2010)Cite this article

Our data suggest that XAF-1 might represent an important determinant in modulating the cytotoxic activity of Nutlin-3 and probably also of other pro-apoptotic drugs in B-CLL cells. In fact, p53del/mut B-CLL samples, which are less responsive to chemotherapeutic or Nutlin-3 treatment than p53wt B-CLL samples, showed low levels of XAF-1 mRNA. Moreover, modulating the steady-state mRNA levels of XAF-1 through IFN-β treatment or silencing the XAF-1 gene significantly affected the Nutlin-3-mediated cytotoxicity in selected samples of primary p53wt and p53del/mut B-CLL as well as in leukemic cell lines. Our current findings are interesting also in light of previous data showing that XAF-1 is a natural antagonist of the inhibitor of apoptosis family proteins,2 which are believed to contribute to cancer progression and to decrease the sensitivity to drug and radiation therapy. In a recent study, Steele et al.7 showed that the transcriptional blockade of p53 through pifithrin-α (PFTα) increases the Nutlin-3 ability to induce apoptosis facilitating the translocation of p53 to mitochondria. Thus, future studies should be aimed at evaluating whether permissive levels of XAF-1 are necessary for an optimal p53-mediated cytotoxic activity at the mitochondrial level. It is also noteworthy that another study has shown that PFTα not only abrogates the p53 transcriptional activity, but also induces the transcriptional activity of XAF-1 expression,8 further suggesting that XAF-1 levels are an important determinant in the cytotoxic activity of p53. In conclusion, although Nutlin-3 has still not been tested in vivo in B-CLL, drugs able to increase the levels of XAF-1 should be further considered for future therapeutic combinations in the treatment of B-CLL with either Nutlin-3 or other chemotherapeutic drugs that are able to activate the p53 pathway, such as fludarabine.

The authors declare no conflict of interest.

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Acknowledgements

This study was supported by grants from the Italian Association for Cancer Research (AIRC) and Beneficientia Foundation (both to GZ).

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Authors and Affiliations

  1. Department of Morphology and Embryology, University of Ferrara, Ferrara, Italy

    P Secchiero, M G di Iasio, E Melloni, R Voltan, C Celeghini & G Zauli

  2. Division of Hematology and Bone Marrow Transplantation, Department of Medical and Morphological Research, University Hospital, Udine, Italy

    M Tiribelli

  3. Clinical and Experimental Hematology Research Unit, Centro di Riferimento Oncologico, IRCCS, Aviano (PN), Italy

    M Dal Bo & V Gattei

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Correspondence to G Zauli.

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Secchiero, P., di Iasio, M., Melloni, E. et al. The expression levels of the pro-apoptotic XAF-1 gene modulate the cytotoxic response to Nutlin-3 in B chronic lymphocytic leukemia. Leukemia 24, 480–483 (2010). https://doi.org/10.1038/leu.2009.215

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