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p53 and Notch signaling in chronic lymphocytic leukemia: clues to identifying novel therapeutic strategies

Leukemia volume 25, pages 1400–1407 (2011)Cite this article

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Abstract

The p53 tumor suppressor protein has a key role in the induction of apoptosis of chronic lymphocytic leukemia (CLL) cells. Abnormalities within the p53 pathway identify a subset of patients with a poor prognosis. This review describes recent advances in understanding the mechanisms that regulate p53 levels and the role of p53 in the control of the cell cycle and of apoptosis. The classical model of p53-mediated apoptosis emphasizes the transcriptional activation of proapoptotic genes. In contrast, a novel model emphasizes p53's non-transcriptional actions as the major route of apoptosis induction, whereas its transcriptional arm predominantly upregulates antiapoptotic genes, thus providing a negative feedback mechanism that limits apoptosis. Further studies have identified the Notch pathway as a candidate p53-induced antiapoptotic mechanism. In contrast to the classical model, the novel model predicts that pharmacological inhibition of p53's transcriptional function or of the Notch signaling pathway will augment apoptosis induction by cytotoxic agents. Therapeutic strategies based on the novel model, which we review here for the first time, may significantly augment the antitumor actions of cytotoxic agents in CLL and in other malignancies.

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Acknowledgements

We thank Leukaemia and Lymphoma Research, UK, and the Dreyfus and Irvine Sellar Foundations for generously supporting work in our laboratory.

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  1. A J Steele

    Present address: Current address: Cancer Sciences Division, Somers Building, Southampton General Hospital (MP824), Southampton, SO16 6YD, UK.,

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  1. Department of Haematology, Cancer Institute, University College Hospital Medical School, London, UK

    R G Wickremasinghe, A G Prentice & A J Steele

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Wickremasinghe, R., Prentice, A. & Steele, A. p53 and Notch signaling in chronic lymphocytic leukemia: clues to identifying novel therapeutic strategies. Leukemia 25, 1400–1407 (2011). https://doi.org/10.1038/leu.2011.103

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