title: Both leukaemic and normal peripheral B lymphoid cells are highly sensitive to the selective pharmacological inhibition of prosurvival Bcl-2 with ABT-199.
abstract: Overexpression of the prosurvival protein Bcl-2 marks many B-lymphoid malignancies and contributes to resistance to many commonly used chemotherapeutic agents. The first effective BH3 mimetic inhibitors of Bcl-2, ABT-737 and navitoclax, also target Bcl-xL, causing dose-limiting thrombocytopenia. This prompted the development of the Bcl-2-selective antagonist, ABT-199. Here we show that in lymphoid cells, ABT-199 specifically causes Bax/Bak-mediated apoptosis that is triggered principally by the initiator BH3-only protein Bim. As expected, malignant cells isolated from patients with chronic lymphocytic leukaemia are highly sensitive to ABT-199. However, we found that normal, untransformed mature B cells are also highly sensitive to ABT-199, both in vitro and in vivo. By contrast, the B-cell precursors are largely spared, as are cells of myeloid origin. These results pinpoint the probable impact of the pharmacological inhibition of Bcl-2 by ABT-199 on the normal mature haemopoietic cell lineages in patients, and have implications for monitoring during ABT-199 therapy as well as for the clinical utility of this very promising targeted agent.
authors.affiliation: 1] The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia [2] Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia [3] Royal Children's Hospital, Parkville, VIC, Australia.
authors.forename: S L
authors.identifier: 0000000290848974
authors.initials: SL
authors.lastname: Khaw
authors.affiliation: 1] The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia [2] Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.
authors.forename: D
authors.initials: D
authors.lastname: Mérino
authors.affiliation: 1] The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia [2] Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia [3] Department of Clinical Haematology and BMT, Royal Melbourne Hospital, Parkville, VIC, Australia [4] Faculty of Medicine, Department of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, VIC, Australia.
authors.forename: M A
authors.initials: MA
authors.lastname: Anderson
authors.affiliation: 1] The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia [2] Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.
authors.forename: S P
authors.initials: SP
authors.lastname: Glaser
authors.affiliation: 1] The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia [2] Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.
authors.forename: P
authors.initials: P
authors.lastname: Bouillet
authors.affiliation: 1] The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia [2] Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia [3] Department of Clinical Haematology and BMT, Royal Melbourne Hospital, Parkville, VIC, Australia [4] Faculty of Medicine, Department of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, VIC, Australia [5] Victorian Comprehensive Cancer Centre, Parkville, VIC, Australia.
authors.forename: A W
authors.initials: AW
authors.lastname: Roberts
authors.affiliation: 1] The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia [2] Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.
authors.forename: D C S
authors.initials: DC
authors.lastname: Huang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000502:physiology; D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D015153:Blotting, Western; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D064368:Healthy Volunteers; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000187:drug effects / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000502:physiology; D023041:Xenograft Model Antitumor Assays; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000502:physiology; D051028:bcl-2-Associated X Protein / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; C494773:Bak1 protein, mouse; C494827:Bax protein, mouse; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C435486:Bmf protein, mouse; D019086:Bridged Bicyclo Compounds, Heterocyclic; D008565:Membrane Proteins; C488588:PUMA protein, mouse; C408009:Pmaip1 protein, mouse; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D025521:Tumor Suppressor Proteins; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; C579720:venetoclax