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Blood, 15 May 2006, Vol. 107, No. 10, pp. 4122-4129.
Prepublished online as a Blood First Edition Paper on February 7, 2006; DOI 10.1182/blood-2005-11-4465.
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NEOPLASIA
Functional integrity of the p53-mediated apoptotic pathway induced by the nongenotoxic agent nutlin-3 in B-cell chronic lymphocytic leukemia (B-CLL)
Paola Secchiero,
Elisa Barbarotto,
Mario Tiribelli,
Carlotta Zerbinati,
Maria Grazia di Iasio,
Arianna Gonelli,
Francesco Cavazzini,
Diana Campioni,
Renato Fanin,
Antonio Cuneo, and
Giorgio Zauli
From the Department of Morphology and Embryology, Human Anatomy Section, University of Ferrara, and the Department of Biomedical Sciences and Advanced Therapies, Section of Hematology, University of Ferrara-Arcispedale S. Anna, Ferrara, Italy; the Department of Medical and Morphological Researches, Division of Hematology and Bone Marrow Transplantation, University Hospital, Udine, Italy; and the Department of Normal Human Morphology, University of Trieste, Trieste, Italy.
Deletions and/or mutations of p53 are relatively rare and late events in the natural history of B-cell chronic lymphocytic leukemia (B-CLL). However, it is unknown whether p53 signaling is functional in B-CLL and if targeted nongenotoxic activation of the p53 pathway by using nutlin-3, a small molecule inhibitor of the p53/MDM2 interaction, is sufficient to kill B-CLL cells. In vitro treatment with nutlin-3 induced a significant cytotoxicity on primary CD19+ B-CLL cells, but not on normal CD19+ B lymphocytes, peripheral-blood mononuclear cells, or bone marrow hematopoietic progenitors. Among 29 B-CLL samples examined, only one was resistant to nutlin-3–mediated cytotoxicity. The induction of p53 by nutlin-3 in B-CLL samples was accompanied by alterations of the mitochondrial potential and activation of the caspase-dependent apoptotic pathway. Among several genes related to the p53 pathway, nutlin-3 up-regulated the steady-state mRNA levels of PCNA, CDKN1A/p21, GDF15, TNFRSF10B/TRAIL-R2, TP53I3/PIG3, and GADD45. This profile of gene activation showed a partial overlapping with that induced by the genotoxic drug fludarabine. Moreover, nutlin-3 synergized with both fludarabine and chlorambucil in inducing B-CLL apoptosis. Our data strongly suggest that nutlin-3 should be further investigated for clinical applications in the treatment of B-CLL.
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