Journal article
Platelet production proceeds independently of the intrinsic and extrinsic apoptosis pathways
EC Josefsson, DL Burnett, M Lebois, MA Debrincat, MJ White, KJ Henley, RM Lane, D Moujalled, SP Preston, LA O'Reilly, M Pellegrini, D Metcalf, A Strasser, BT Kile
Nature Communications | Published : 2014
DOI: 10.1038/ncomms4455
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...
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Funding Acknowledgements
The authors thank J. Corbin, L. Di Rago and L. Whitehead for excellent technical assistance; S. Green, E. Lanera, K. McGregor, S. Ross, M. Dayton, K. Stoev and L. Wilkins for outstanding animal husbandry; and T. Mak, R. Flavell, D. Huang, J. Silke, L. Coultas and M. Takiguchi for mice and reagents. This work was supported by Project Grants (575535 and 1009145), Program Grants (461219, 461221 and 1016647), Fellowships (A. S. and B. T. K.) and an Independent Research Institutes Infrastructure Support Scheme Grant (361646) from the National Health and Medical Research Council (Australia); a fellowship from the Sylvia and Charles Viertel Foundation (B. T. K.), a SCOR grant (A. S.) and a fellowship (E.C.J) from the Leukemia & Lymphoma Society; a fellowship (D. M.) and a grant (A. S.) from the Cancer Council of Victoria; the Australian Cancer Research Foundation, and a Victorian State Government Operational Infrastructure Support Grant.