Mdm2 inhibitor Nutlin-3a induces p53-mediated apoptosis by transcription-dependent and transcription-independent mechanisms and may overcome Atm-mediated resistance to fludarabine in chronic lymphocytic leukemia.

摘要: Although TP53 mutations are rare in B-cell chronic lymphocytic leukemia (CLL), Mdm2 overexpression has been reported as an alternative cause of p53 dysfunction. We investigated the potential therapeutic use nongenotoxic activation by a small-molecule antagonist Mdm2, Nutlin-3a, CLL. Nutlin-3a induced significant apoptosis 30 (91%) 33 samples from previously untreated patients with CLL; all resistant had mutations. Low levels Atm (ataxia telangiectasia mutated) or high (murine double minute 2) did not prevent inducing apoptosis. used transcription-dependent and transcription-independent pathways to induce p53-mediated Predominant pathway more pronounced than that pathway, suggesting is sufficient initiate Combination treatment fludarabine synergistically increased levels, conformational change Bax wild-type cells but mutant p53. The synergistic apoptotic effect was maintained low were resistant. Results suggest targeting Mdm2-p53 interaction provides novel strategy for