title: Platelet production proceeds independently of the intrinsic and extrinsic apoptosis pathways.
abstract: BH3 mimetic drugs that target BCL-2 family pro-survival proteins to induce tumour cell apoptosis represent a new era in cancer therapy. Clinical trials of navitoclax (ABT-263, which targets BCL-2, BCL-XL and BCL-W) have shown great promise, but encountered dose-limiting thrombocytopenia. Recent work has demonstrated that this is due to the inhibition of BCL-XL, which is essential for platelet survival. These findings raise new questions about the established model of platelet shedding by megakaryocytes, which is thought to be an apoptotic process. Here we generate mice with megakaryocyte-specific deletions of the essential mediators of extrinsic (Caspase-8) and intrinsic (BAK/BAX) apoptosis. We show that megakaryocytes possess a Fas ligand-inducible extrinsic apoptosis pathway. However, Fas activation does not stimulate platelet production, rather, it triggers Caspase-8-mediated killing. Combined loss of Caspase-8/BAK/BAX does not impair thrombopoiesis, but can protect megakaryocytes from death in mice infected with lymphocytic choriomeningitis virus. Thus, apoptosis is dispensable for platelet biogenesis.
authors.affiliation: 1] The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia [2] Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia [3].
authors.forename: Emma C
authors.initials: EC
authors.lastname: Josefsson
authors.affiliation: 1] The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia [2] Department of Veterinary Science, The University of Sydney, New South Wales 2006, Australia [3].
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Burnett
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia.
authors.forename: Marion
authors.initials: M
authors.lastname: Lebois
authors.affiliation: 1] The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia [2] Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia.
authors.forename: Marlyse A
authors.initials: MA
authors.lastname: Debrincat
authors.affiliation: 1] The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia [2] Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: White
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia.
authors.forename: Katya J
authors.initials: KJ
authors.lastname: Henley
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia.
authors.forename: Rachael M
authors.initials: RM
authors.lastname: Lane
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia.
authors.forename: Diane
authors.initials: D
authors.lastname: Moujalled
authors.affiliation: 1] The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia [2] Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia.
authors.forename: Simon P
authors.initials: SP
authors.lastname: Preston
authors.affiliation: 1] The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia [2] Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia.
authors.forename: Lorraine A
authors.initials: LA
authors.lastname: O'Reilly
authors.affiliation: 1] The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia [2] Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia.
authors.forename: Marc
authors.initials: M
authors.lastname: Pellegrini
authors.affiliation: 1] The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia [2] Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia.
authors.forename: Donald
authors.initials: D
authors.lastname: Metcalf
authors.affiliation: 1] The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia [2] Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia.
authors.forename: Andreas
authors.initials: A
authors.lastname: Strasser
authors.affiliation: 1] The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia [2] Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia.
authors.forename: Benjamin T
authors.initials: BT
authors.lastname: Kile
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D015153:Blotting, Western; D053181:Caspase 8 / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D008297:Male; D051379:Mice; D051381:Rats; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D013921:Thrombocytopenia / Q000378:metabolism
chemical_list: D000814:Aniline Compounds; D013449:Sulfonamides; D053181:Caspase 8; C528561:navitoclax