Platelet production proceeds independently of the intrinsic and extrinsic apoptosis pathways

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...

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Bibliographic Details
Published in:Nature communications 2014-03, Vol.5 (1), p.3455-3455, Article 3455
Main Authors: Josefsson, Emma C, Burnett, Deborah L, Lebois, Marion, Debrincat, Marlyse A, White, Michael J, Henley, Katya J, Lane, Rachael M, Moujalled, Diane, Preston, Simon P, O'Reilly, Lorraine A, Pellegrini, Marc, Metcalf, Donald, Strasser, Andreas, Kile, Benjamin T
Format: Article
Language:English
Subjects:
Aniline Compounds - pharmacology
Animals
Apoptosis - physiology
Blood Platelets - drug effects
Blood Platelets - metabolism
Blotting, Western
Caspase 8 - metabolism
Electrophoresis, Polyacrylamide Gel
Female
Male
Mice
Rats
Signal Transduction
Sulfonamides - pharmacology
Thrombocytopenia - metabolism
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Summary: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.
ISSN:2041-1723
2041-1723
DOI:10.1038/ncomms4455