Megakaryocytes possess a functional intrinsic apoptosis pathway that must be restrained to survive and produce platelets

Emma C. Josefsson, Chloe James, Katya J. Henley, Marlyse A. Debrincat, Kelly L. Rogers, Mark R. Dowling, Michael J. White, Elizabeth A. Kruse, Rachael M. Lane, Sarah Ellis, Paquita Nurden, Kylie D. Mason, Lorraine A. O'Reilly, Andrew W. Roberts, Donald Metcalf, David C. S. Huang, Benjamin T. Kile

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Abstract

It is believed that megakaryocytes undergo a specialized form of apoptosis to shed platelets. Conversely, a range of pathophysiological insults, including chemotherapy, are thought to cause thrombocytopenia by inducing the apoptotic death of megakaryocytes and their progenitors. To resolve this paradox, we generated mice with hematopoietic- or megakaryocyte-specific deletions of the essential mediators of apoptosis, Bak and Bax. We found that platelet production was unperturbed. In stark contrast, deletion of the prosurvival protein Bcl-xL resulted in megakaryocyte apoptosis and a failure of platelet shedding. This could be rescued by deletion of Bak and Bax. We examined the effect on megakaryocytes of three agents that activate the intrinsic apoptosis pathway in other cell types: etoposide, staurosporine, and the BH3 mimetic ABT-737. All three triggered mitochondrial damage, caspase activation, and cell death. Deletion of Bak and Bax rendered megakaryocytes resistant to etoposide and ABT-737. In vivo, mice with a Bak−/− Bax−/−hematopoietic system were protected against thrombocytopenia induced by the chemotherapeutic agent carboplatin. Thus, megakaryocytes do not activate the intrinsic pathway to generate platelets; rather, the opposite is true: they must restrain it to survive and progress safely through proplatelet formation and platelet shedding.

Original languageEnglish
Pages (from-to)2017-2031
Number of pages15
JournalJournal of Experimental Medicine
Volume208
Issue number10
DOIs
Publication statusPublished - 26 Sep 2011
Externally publishedYes

Cite this

Josefsson, Emma C. ; James, Chloe ; Henley, Katya J. ; Debrincat, Marlyse A. ; Rogers, Kelly L. ; Dowling, Mark R. ; White, Michael J. ; Kruse, Elizabeth A. ; Lane, Rachael M. ; Ellis, Sarah ; Nurden, Paquita ; Mason, Kylie D. ; O'Reilly, Lorraine A. ; Roberts, Andrew W. ; Metcalf, Donald ; Huang, David C. S. ; Kile, Benjamin T. / Megakaryocytes possess a functional intrinsic apoptosis pathway that must be restrained to survive and produce platelets. In: Journal of Experimental Medicine. 2011 ; Vol. 208, No. 10. pp. 2017-2031.
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title = "Megakaryocytes possess a functional intrinsic apoptosis pathway that must be restrained to survive and produce platelets",
abstract = "It is believed that megakaryocytes undergo a specialized form of apoptosis to shed platelets. Conversely, a range of pathophysiological insults, including chemotherapy, are thought to cause thrombocytopenia by inducing the apoptotic death of megakaryocytes and their progenitors. To resolve this paradox, we generated mice with hematopoietic- or megakaryocyte-specific deletions of the essential mediators of apoptosis, Bak and Bax. We found that platelet production was unperturbed. In stark contrast, deletion of the prosurvival protein Bcl-xL resulted in megakaryocyte apoptosis and a failure of platelet shedding. This could be rescued by deletion of Bak and Bax. We examined the effect on megakaryocytes of three agents that activate the intrinsic apoptosis pathway in other cell types: etoposide, staurosporine, and the BH3 mimetic ABT-737. All three triggered mitochondrial damage, caspase activation, and cell death. Deletion of Bak and Bax rendered megakaryocytes resistant to etoposide and ABT-737. In vivo, mice with a Bak−/− Bax−/−hematopoietic system were protected against thrombocytopenia induced by the chemotherapeutic agent carboplatin. Thus, megakaryocytes do not activate the intrinsic pathway to generate platelets; rather, the opposite is true: they must restrain it to survive and progress safely through proplatelet formation and platelet shedding.",
author = "Josefsson, {Emma C.} and Chloe James and Henley, {Katya J.} and Debrincat, {Marlyse A.} and Rogers, {Kelly L.} and Dowling, {Mark R.} and White, {Michael J.} and Kruse, {Elizabeth A.} and Lane, {Rachael M.} and Sarah Ellis and Paquita Nurden and Mason, {Kylie D.} and O'Reilly, {Lorraine A.} and Roberts, {Andrew W.} and Donald Metcalf and Huang, {David C. S.} and Kile, {Benjamin T.}",
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Josefsson, EC, James, C, Henley, KJ, Debrincat, MA, Rogers, KL, Dowling, MR, White, MJ, Kruse, EA, Lane, RM, Ellis, S, Nurden, P, Mason, KD, O'Reilly, LA, Roberts, AW, Metcalf, D, Huang, DCS & Kile, BT 2011, 'Megakaryocytes possess a functional intrinsic apoptosis pathway that must be restrained to survive and produce platelets', Journal of Experimental Medicine, vol. 208, no. 10, pp. 2017-2031. https://doi.org/10.1084/jem.20110750

Megakaryocytes possess a functional intrinsic apoptosis pathway that must be restrained to survive and produce platelets. / Josefsson, Emma C.; James, Chloe; Henley, Katya J.; Debrincat, Marlyse A.; Rogers, Kelly L.; Dowling, Mark R.; White, Michael J.; Kruse, Elizabeth A.; Lane, Rachael M.; Ellis, Sarah; Nurden, Paquita ; Mason, Kylie D.; O'Reilly, Lorraine A.; Roberts, Andrew W.; Metcalf, Donald; Huang, David C. S.; Kile, Benjamin T.

In: Journal of Experimental Medicine, Vol. 208, No. 10, 26.09.2011, p. 2017-2031.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Josefsson, Emma C.

AU - James, Chloe

AU - Henley, Katya J.

AU - Debrincat, Marlyse A.

AU - Rogers, Kelly L.

AU - Dowling, Mark R.

AU - White, Michael J.

AU - Kruse, Elizabeth A.

AU - Lane, Rachael M.

AU - Ellis, Sarah

AU - Nurden, Paquita

AU - Mason, Kylie D.

AU - O'Reilly, Lorraine A.

AU - Roberts, Andrew W.

AU - Metcalf, Donald

AU - Huang, David C. S.

AU - Kile, Benjamin T.

PY - 2011/9/26

Y1 - 2011/9/26

N2 - It is believed that megakaryocytes undergo a specialized form of apoptosis to shed platelets. Conversely, a range of pathophysiological insults, including chemotherapy, are thought to cause thrombocytopenia by inducing the apoptotic death of megakaryocytes and their progenitors. To resolve this paradox, we generated mice with hematopoietic- or megakaryocyte-specific deletions of the essential mediators of apoptosis, Bak and Bax. We found that platelet production was unperturbed. In stark contrast, deletion of the prosurvival protein Bcl-xL resulted in megakaryocyte apoptosis and a failure of platelet shedding. This could be rescued by deletion of Bak and Bax. We examined the effect on megakaryocytes of three agents that activate the intrinsic apoptosis pathway in other cell types: etoposide, staurosporine, and the BH3 mimetic ABT-737. All three triggered mitochondrial damage, caspase activation, and cell death. Deletion of Bak and Bax rendered megakaryocytes resistant to etoposide and ABT-737. In vivo, mice with a Bak−/− Bax−/−hematopoietic system were protected against thrombocytopenia induced by the chemotherapeutic agent carboplatin. Thus, megakaryocytes do not activate the intrinsic pathway to generate platelets; rather, the opposite is true: they must restrain it to survive and progress safely through proplatelet formation and platelet shedding.

AB - It is believed that megakaryocytes undergo a specialized form of apoptosis to shed platelets. Conversely, a range of pathophysiological insults, including chemotherapy, are thought to cause thrombocytopenia by inducing the apoptotic death of megakaryocytes and their progenitors. To resolve this paradox, we generated mice with hematopoietic- or megakaryocyte-specific deletions of the essential mediators of apoptosis, Bak and Bax. We found that platelet production was unperturbed. In stark contrast, deletion of the prosurvival protein Bcl-xL resulted in megakaryocyte apoptosis and a failure of platelet shedding. This could be rescued by deletion of Bak and Bax. We examined the effect on megakaryocytes of three agents that activate the intrinsic apoptosis pathway in other cell types: etoposide, staurosporine, and the BH3 mimetic ABT-737. All three triggered mitochondrial damage, caspase activation, and cell death. Deletion of Bak and Bax rendered megakaryocytes resistant to etoposide and ABT-737. In vivo, mice with a Bak−/− Bax−/−hematopoietic system were protected against thrombocytopenia induced by the chemotherapeutic agent carboplatin. Thus, megakaryocytes do not activate the intrinsic pathway to generate platelets; rather, the opposite is true: they must restrain it to survive and progress safely through proplatelet formation and platelet shedding.

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