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The small molecule inhibitor of the MDM2/p53 interaction Nutlin-3 significantly up-regulated the steady-state mRNA and protein levels of Notch1 in TP53^wild-type (OCI, SKW6.4) but not in TP53^deleted (HL-60) or TP53^mutated (BJAB) leukemic cell lines. A direct demonstration that NOTCH1 was a transcriptional target of p53 in leukemic cells was obtained in experiments carried out with siRNA for p53. Moreover, inhibition of Notch1 expression using Notch1-specific siRNA significantly increased cytotoxicity in TP53^wild-type leukemic cells. Of note, Nutlin-3 up-regulated Notch1 expression also in primary TP53^wild-type B-chronic lymphocytic leukemia (B-CLL) cells and the combined use of Nutlin-3 plus pharmacological γ-secretase inhibitors of the Notch signaling showed a synergistic cytotoxicity in both TP53^wild-type leukemic cell lines and primary B-CLL cells. A potential drawback of γ-secretase inhibitors was …