Platelet production proceeds independently of the intrinsic and extrinsic apoptosis pathways
- Josefsson, EC; Burnett, DL; Lebois, M; Debrincat, MA; White, MJ; Henley, KJ; Lane, RM; Moujalled, D; Preston, SP; O'Reilly, LA; Pellegrini, M; Metcalf, D; Strasser, A; Kile, BT;
- Journal Title
- Nature Communications
- Publication Type
- Journal Article
- 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.
- WEHI Research Division(s)
- Infection And Immunity; Chemical Biology; Cell Signalling And Cell Death; Cancer And Haematology; Molecular Genetics Of Cancer
- Publisher's Version
- Rights Notice
- © 2014 Macmillan Publishers Limited. All Rights Reserved.
Creation Date: 2014-06-12 10:38:03Last Modified: 2018-05-01 02:06:07