title: Induction of TAp73 by platinum-based compounds to overcome drug resistance in p53 dysfunctional chronic lymphocytic leukemia.
abstract: In chronic lymphocytic leukemia (CLL), strategies to overcome drug resistance due to p53 dysfunction are highly needed. Platinum-based compounds such as cisplatinum (CDDP) are active in fludarabine-refractory CLL through a largely unknown mechanism. We analyzed the mechanism of action of CDDP in the context of p53 dysfunctionality. In vitro treatment with CDDP did not induce death in quiescent CLL cells, but did induce apoptosis in CD40-ligand (and CpG) stimulated and proliferating cells, irrespective of p53 function. In the p53 dysfunctional prolymphocytic cell-line MEC1, CDDP treatment resulted in apoptosis, cell cycle arrest and ABL1-dependent expression of TAp73, CDKN1A, PUMA and BID. TAp73 RNA-interference decreased sensitivity to CDDP. Finally, both in vitro stimulated CLL cells and lymph node (LN) derived CLL cells showed increased TAp73 expression in comparison with quiescent peripheral blood derived cells. Activity of CDDP may therefore be mediated by TAp73, especially in the context of activation such as occurs in the LN microenvironment.
authors.affiliation: a Department of Hematology , Academic Medical Center , Amsterdam , The Netherlands.|b Lymphoma and Myeloma Center Amsterdam (LYMMCARE) , Amsterdam , The Netherlands.
authors.forename: Sanne H
authors.initials: SH
authors.lastname: Tonino
authors.affiliation: c Laboratory for Experimental Immunology, Academic Medical Center , Amsterdam , The Netherlands.
authors.forename: Chantal E
authors.initials: CE
authors.lastname: Mulkens
authors.affiliation: c Laboratory for Experimental Immunology, Academic Medical Center , Amsterdam , The Netherlands.
authors.forename: Jacoline
authors.initials: J
authors.lastname: van Laar
authors.affiliation: c Laboratory for Experimental Immunology, Academic Medical Center , Amsterdam , The Netherlands.
authors.forename: Ingrid A M
authors.initials: IA
authors.lastname: Derks
authors.affiliation: d Division of Hematology-Oncology, Department of Medicine , Moores Cancer Center, University of California , San Diego, La Jolla , CA , USA.
authors.forename: Guangli
authors.initials: G
authors.lastname: Suo
authors.affiliation: e Department of Internal Medicine , Ikazia Hospital , Rotterdam , The Netherlands.
authors.forename: Fransien
authors.initials: F
authors.lastname: Croon-de Boer
authors.affiliation: a Department of Hematology , Academic Medical Center , Amsterdam , The Netherlands.|b Lymphoma and Myeloma Center Amsterdam (LYMMCARE) , Amsterdam , The Netherlands.
authors.forename: Marinus H J
authors.initials: MH
authors.lastname: van Oers
authors.affiliation: b Lymphoma and Myeloma Center Amsterdam (LYMMCARE) , Amsterdam , The Netherlands.|c Laboratory for Experimental Immunology, Academic Medical Center , Amsterdam , The Netherlands.
authors.forename: Eric
authors.initials: E
authors.lastname: Eldering
authors.affiliation: d Division of Hematology-Oncology, Department of Medicine , Moores Cancer Center, University of California , San Diego, La Jolla , CA , USA.
authors.forename: Jean Y
authors.initials: JY
authors.lastname: Wang
authors.affiliation: a Department of Hematology , Academic Medical Center , Amsterdam , The Netherlands.|b Lymphoma and Myeloma Center Amsterdam (LYMMCARE) , Amsterdam , The Netherlands.
authors.forename: Arnon P
authors.initials: AP
authors.lastname: Kater
mesh_terms: D000954:Antigens, Surface / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D051023:BH3 Interacting Domain Death Agonist Protein / Q000235:genetics / Q000378:metabolism; D015415:Biomarkers; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D055785:Gene Knockdown Techniques; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010984:Platinum / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics / Q000378:metabolism; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D000954:Antigens, Surface; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; D015415:Biomarkers; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D010984:Platinum; D016315:Proto-Oncogene Proteins c-abl; D002945:Cisplatin
keywords: CDDP; Chronic lymphocytic leukemia; TAp73; drug resistance; p53