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

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&#39;Reilly, LA; Roberts, AW; Metcalf, D; Huang, DCS; Kile, BT

Author(s): 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;
Details: Publication Year 2011-09-26,Volume 208,Issue #10,Page 2017-2031
Journal Title: JOURNAL OF EXPERIMENTAL MEDICINE
Publication Type: Journal Article
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-x(L) 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.
Publisher: ROCKEFELLER UNIV PRESS
Keywords: TRANSCRIPTION FACTOR NF-E2; CELL-DEATH; BCL-X; MICE LACKING; IN-VIVO; THROMBOCYTOPENIC PURPURA; CASPASE ACTIVATION; DEFICIENT MICE; BONE-MARROW; LIFE-SPAN
Research Division(s): Cancer And Haematology; Molecular Medicine; Molecular Genetics Of Cancer; Chemical Biology; Immunology
Publisher's Version: https://doi.org/10.1084/jem.20110750
Open Access at Publisher's Site: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3182050/
Terms of Use/Rights Notice: Copyright © 2011 Josefsson et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

Creation Date: 2011-09-26 12:00:00