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, Benjamin T. Kile

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Article number3455
Number of pages14
JournalNature Communications
Volume5
DOIs
Publication statusPublished - 17 Mar 2014
Externally publishedYes

Keywords

  • cell signalling
  • platelets

Cite this

Josefsson, E. C., Burnett, D. L., Lebois, M., Debrincat, M. A., White, M. J., Henley, K. J., ... Kile, B. T. (2014). Platelet production proceeds independently of the intrinsic and extrinsic apoptosis pathways. Nature Communications, 5, [3455]. https://doi.org/10.1038/ncomms4455
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. / Platelet production proceeds independently of the intrinsic and extrinsic apoptosis pathways. In: Nature Communications. 2014 ; Vol. 5.
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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 2014, 'Platelet production proceeds independently of the intrinsic and extrinsic apoptosis pathways', Nature Communications, vol. 5, 3455. https://doi.org/10.1038/ncomms4455

Platelet production proceeds independently of the intrinsic and extrinsic apoptosis pathways. / 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.

In: Nature Communications, Vol. 5, 3455, 17.03.2014.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Josefsson, Emma C

AU - Burnett, Deborah L.

AU - Lebois, Marion

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AU - Henley, Katya J

AU - Lane, Rachael M

AU - Moujalled, Diane

AU - Preston, Simon P.

AU - O'Reilly, Lorraine A

AU - Pellegrini, Marc

AU - Metcalf, Donald

AU - Strasser, Andreas

AU - Kile, Benjamin T.

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N2 - 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.

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Josefsson EC, Burnett DL, Lebois M, Debrincat MA, White MJ, Henley KJ et al. Platelet production proceeds independently of the intrinsic and extrinsic apoptosis pathways. Nature Communications. 2014 Mar 17;5. 3455. https://doi.org/10.1038/ncomms4455