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

被引:142
作者
Secchiero, Paola
Barbarotto, Elisa
Tiribelli, Mario
Zerbinati, Carlotta
di Iasio, Maria Grazia
Gonelli, Arianna
Cavazzini, Francesco
Campioni, Diana
Fanin, Renato
Cuneo, Antonio
Zauli, Giorgio
机构
[1] Univ Ferrara, Dept Morphol & Embryol, Human Anat Sect, I-44100 Ferrara, Italy
[2] Univ Ferrara, Arcispedale S Anna, Dept Biomed Sci & Adv Therapies, Sect Hematol, I-44100 Ferrara, Italy
[3] Univ Hosp, Dept Med & Morphol Res, Div Hematol & Bone Marrow Transplantat, Udine, Italy
[4] Univ Trieste, Dept Normal Human Morphol, Trieste, Italy
关键词
D O I
10.1182/blood-2005-11-4465
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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,TP5313/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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页码:4122 / 4129
页数:8
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