Platelet production proceeds independently of the intrinsic and extrinsic apoptosis pathways

Emma C. Josefsson, Deborah L. Burnett, Marion Lebois, Marlyse A. Debrincat, Michael J. White, Katya J. Henley, Rachael M. Lane, Diane Moujalled, Simon P. Preston, Lorraine A. O’Reilly, Marc Pellegrini, Donald Metcalf, Andreas Strasser and Benjamin T. Kile ()
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Emma C. Josefsson: The Walter and Eliza Hall Institute of Medical Research
Deborah L. Burnett: The Walter and Eliza Hall Institute of Medical Research
Marion Lebois: The Walter and Eliza Hall Institute of Medical Research
Marlyse A. Debrincat: The Walter and Eliza Hall Institute of Medical Research
Michael J. White: The Walter and Eliza Hall Institute of Medical Research
Katya J. Henley: The Walter and Eliza Hall Institute of Medical Research
Rachael M. Lane: The Walter and Eliza Hall Institute of Medical Research
Diane Moujalled: The Walter and Eliza Hall Institute of Medical Research
Simon P. Preston: The Walter and Eliza Hall Institute of Medical Research
Lorraine A. O’Reilly: The Walter and Eliza Hall Institute of Medical Research
Marc Pellegrini: The Walter and Eliza Hall Institute of Medical Research
Donald Metcalf: The Walter and Eliza Hall Institute of Medical Research
Andreas Strasser: The Walter and Eliza Hall Institute of Medical Research
Benjamin T. Kile: The Walter and Eliza Hall Institute of Medical Research

Nature Communications, 2014, vol. 5, issue 1, 1-14

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms4455

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