CD154 induces p73 to overcome the resistance to apoptosis of chronic lymphocytic leukemia cells lacking functional p53

Intravenous infusion of autologous chronic lymphocytic leukemia (CLL) cells transduced with an adenovirus encoding CD40-ligand (CD154) caused rapid reductions in leukemia-cell counts and lymphnode size. We hypothesized that CD40-ligation via CD154 sensitized CLL cells to death-receptor-mediated apoptosis. We found that CD154-expressing cells induced expression of CD95 and the BH3-interacting-domain death agonist (Bid) in CLL, regardless of whether the leukemia cells had functional p53. Such treatment also induced p73, a p53-related transcription factor regulated by c-Abl kinase, and enhanced the sensitivity to fludarabine (F-ara-A) of CLL cells lacking functional p53. Transduction of CLL cells with an adenovirus encoding p73 also induced Bid and CD95 and enhanced the sensitivity to F-ara-A of p53-deficient CLL cells. However, inhibition of c-Abl with imatinib suppressed CD154-induced expression of p73, p73-induced expression of Bid and CD95, and blocked the sensitization of p53-deficient CLL cells to CD95-mediated or F-ara-A-induced apoptosis. Conversely, CLL cells transduced with an imatinib-resistant c-Abl mutant could be induced by CD154 to express p73 and Bid even when treated with imatinib. These results indicate that CD154 can sensitize leukemia cells to apoptosis via the c-Abl-dependent activation of p73 and mitigate the resistance of p53-deficient CLL cells to anticancer drug therapy