title: Therapeutic Response to Non-genotoxic Activation of p53 by Nutlin3a Is Driven by PUMA-Mediated Apoptosis in Lymphoma Cells.
abstract: Nutlin3a is a small-molecule antagonist of MDM2 that promotes non-genotoxic activation of p53 through p53 protein stabilization and transactivation of p53 target genes. Nutlin3a is the forerunner of a class of cancer therapeutics that have reached clinical trials. Using transgenic and gene-targeted mouse models lacking the critical p53 target genes, p21, Puma, and Noxa, we found that only loss of PUMA conferred profound protection against Nutlin3a-induced killing in both non-transformed lymphoid cells and Eμ-Myc lymphomas in vitro and in vivo. CRISPR/Cas9-mediated targeting of the PUMA gene rendered human hematopoietic cancer cell lines markedly resistant to Nutlin3a-induced cell death. These results demonstrate that PUMA-mediated apoptosis, but not p21-mediated cell-cycle arrest or senescence, is a critical determinant of the therapeutic response to non-genotoxic p53 activation by Nutlin3a. Importantly, in human cancer, PUMA expression may predict patient responses to treatment with MDM2 antagonists.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia.
authors.forename: Liz J
authors.initials: LJ
authors.lastname: Valente
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia; Department of Clinical Haematology and Bone Marrow Transplant Service, The Royal Melbourne Hospital, Parkville, VIC 3050, Australia.
authors.forename: Brandon J
authors.initials: BJ
authors.lastname: Aubrey
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia.
authors.forename: Marco J
authors.initials: MJ
authors.lastname: Herold
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia.
authors.forename: Gemma L
authors.initials: GL
authors.lastname: Kelly
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia.
authors.forename: Lina
authors.initials: L
authors.lastname: Happo
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia.
authors.forename: Clare L
authors.initials: CL
authors.lastname: Scott
authors.affiliation: Cancer Therapeutics Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3002, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC 3002, Australia.
authors.forename: Andrea
authors.initials: A
authors.lastname: Newbold
authors.affiliation: Cancer Therapeutics Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3002, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC 3002, Australia.
authors.forename: Ricky W
authors.initials: RW
authors.lastname: Johnstone
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia.
authors.forename: David C S
authors.initials: DC
authors.lastname: Huang
authors.affiliation: Discovery Oncology, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA.
authors.forename: Lyubomir T
authors.initials: LT
authors.lastname: Vassilev
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia. Electronic address: strasser@wehi.edu.au.
authors.forename: Andreas
authors.initials: A
authors.lastname: Strasser
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D064113:CRISPR-Cas Systems; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008223:Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010879:Piperazines / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D007093:Imidazoles; C488588:PUMA protein, mouse; D010879:Piperazines; C408009:Pmaip1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C482205:nutlin 3; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2