title: CD154 induces p73 to overcome the resistance to apoptosis of chronic lymphocytic leukemia cells lacking functional p53.
abstract: 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.
authors.affiliation: Moores Cancer Center, University of California-San Diego School of Medicine, La Jolla, CA 92093-0663, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Dicker
authors.forename: Arnon P
authors.initials: AP
authors.lastname: Kater
authors.forename: Carlos E
authors.initials: CE
authors.lastname: Prada
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Fukuda
authors.forename: Januario E
authors.initials: JE
authors.lastname: Castro
authors.forename: Guizhen
authors.initials: G
authors.lastname: Sun
authors.forename: Jean Y
authors.initials: JY
authors.lastname: Wang
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Kipps
mesh_terms: D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein / Q000235:genetics; D001549:Benzamides; D019013:CD40 Antigens; D023201:CD40 Ligand / Q000502:physiology*; D002452:Cell Count; D004268:DNA-Binding Proteins / Q000502:physiology*; D015973:Gene Expression Regulation, Leukemic; D006367:HeLa Cells; D006801:Humans; D000068877:Imatinib Mesylate; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000473:pathology*; D008198:Lymph Nodes / Q000473:pathology; D009687:Nuclear Proteins / Q000502:physiology*; D010879:Piperazines / Q000494:pharmacology; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency*; D025521:Tumor Suppressor Proteins / Q000502:physiology*; D019014:fas Receptor / Q000235:genetics
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D001549:Benzamides; D019013:CD40 Antigens; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D010879:Piperazines; D011743:Pyrimidines; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D019014:fas Receptor; D023201:CD40 Ligand; D000068877:Imatinib Mesylate; D016315:Proto-Oncogene Proteins c-abl