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, Giorgio Zauli

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)4122-4129
Number of pages8
JournalBlood
Volume107
Issue number10
DOIs
Publication statusPublished - May 15 2006

ASJC Scopus subject areas

  • Hematology

Fingerprint Dive into the research topics of 'Functional integrity of the p53-mediated apoptotic pathway induced by the nongenotoxic agent nutlin-3 in B-cell chronic lymphocytic leukemia (B-CLL)'. Together they form a unique fingerprint.

Cite this