DOI: 10.1182/blood-2005-11-4465. Functional integrity of the p53-mediated apoptotic pathway induced by the nongenotoxic agent nutlin-3 in B-cell chronic lymphocytic leukemia (B-CLL)

Functional integrity of the p53-mediated apoptotic pathway induced by the nongenotoxic agent nutlin-3 in B-cell chronic lymphocytic leukemia (B-CLL)

10.1182/blood-2005-11-4465

Crossref journal-article

American Society of Hematology

Blood (234)

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.

Bibliography

Secchiero, P., Barbarotto, E., Tiribelli, M., Zerbinati, C., di Iasio, M. G., Gonelli, A., Cavazzini, F., Campioni, D., Fanin, R., Cuneo, A., & Zauli, G. (2006). Functional integrity of the p53-mediated apoptotic pathway induced by the nongenotoxic agent nutlin-3 in B-cell chronic lymphocytic leukemia (B-CLL). Blood, 107(10), 4122â4129.

Authors 11

Paola Secchiero (first)
Elisa Barbarotto (additional)
Mario Tiribelli (additional)
Carlotta Zerbinati (additional)
Maria Grazia di Iasio (additional)
Arianna Gonelli (additional)
Francesco Cavazzini (additional)
Diana Campioni (additional)
Renato Fanin (additional)
Antonio Cuneo (additional)
Giorgio Zauli (additional)

References 40 Referenced 119

Dates

Type	When
Created	19 years, 7 months ago (Jan. 26, 2006, 9:03 p.m.)
Deposited	5 years, 9 months ago (Nov. 19, 2019, 4:47 a.m.)
Indexed	2 months, 3 weeks ago (June 4, 2025, 9:56 p.m.)
Issued	19 years, 3 months ago (May 15, 2006)
Published	19 years, 3 months ago (May 15, 2006)
Published Print	19 years, 3 months ago (May 15, 2006)

Funders 0

None

BibTeX

@article{Secchiero_2006, title={Functional integrity of the p53-mediated apoptotic pathway induced by the nongenotoxic agent nutlin-3 in B-cell chronic lymphocytic leukemia (B-CLL)}, volume={107}, ISSN={1528-0020}, url={http://dx.doi.org/10.1182/blood-2005-11-4465}, DOI={10.1182/blood-2005-11-4465}, number={10}, journal={Blood}, publisher={American Society of Hematology}, author={Secchiero, Paola and Barbarotto, Elisa and Tiribelli, Mario and Zerbinati, Carlotta and di Iasio, Maria Grazia and Gonelli, Arianna and Cavazzini, Francesco and Campioni, Diana and Fanin, Renato and Cuneo, Antonio and Zauli, Giorgio}, year={2006}, month=may, pages={4122–4129} }

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