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https://hdl.handle.net/2440/74143
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Type: | Journal article |
Title: | Mcl-1 and Bcl-xL coordinately regulate megakaryocyte survival |
Author: | Debrincat, M. Josefsson, E. James, C. Henley, K. Ellis, S. Lebois, M. Betterman, K. Lane, R. Rogers, K. White, M. Roberts, A. Harvey, N. Metcalf, D. Kile, B. |
Citation: | Blood, 2012; 119(24):5850-5858 |
Publisher: | Amer Soc Hematology |
Issue Date: | 2012 |
ISSN: | 0006-4971 1528-0020 |
Statement of Responsibility: | Marlyse A. Debrincat, Emma C. Josefsson, Chloé James, Katya J. Henley, Sarah Ellis, Marion Lebois, Kelly L. Betterman, Rachael M. Lane, Kelly L. Rogers, Michael J. White, Andrew W. Roberts, Natasha L. Harvey, Donald Metcalf and Benjamin T. Kile |
Abstract: | Mature megakaryocytes depend on the function of Bcl-x(L), a member of the Bcl-2 family of prosurvival proteins, to proceed safely through the process of platelet shedding. Despite this, loss of Bcl-x(L) does not prevent the growth and maturation of megakaryocytes, suggesting redundancy with other prosurvival proteins. We therefore generated mice with a megakaryocyte-specific deletion of Mcl-1, which is known to be expressed in megakaryocytes. Megakaryopoiesis, platelet production, and platelet lifespan were unperturbed in Mcl-1(Pf4Δ/Pf4Δ) animals. However, treatment with ABT-737, a BH3 mimetic compound that inhibits the prosurvival proteins Bcl-2, Bcl-x(L), and Bcl-w resulted in the complete ablation of megakaryocytes and platelets. Genetic deletion of both Mcl-1 and Bcl-x(L) in megakaryocytes resulted in preweaning lethality. Megakaryopoiesis in Bcl-x(Pf4Δ/Pf4Δ) Mcl-1(Pf4Δ/Pf4Δ) embryos was severely compromised, and these animals exhibited ectopic bleeding. Our studies indicate that the combination of Bcl-x(L) and Mcl-1 is essential for the viability of the megakaryocyte lineage. |
Keywords: | Liver Blood Platelets Megakaryocytes Lymphatic Vessels Fetus Animals Mice, Inbred C57BL Mice Hemorrhage Sulfonamides Biphenyl Compounds Nitrophenols Piperazines Proto-Oncogene Proteins c-bcl-2 Blood Cell Count Cell Count Cell Death Thrombopoiesis Cell Size Cell Survival Organ Specificity Gene Deletion Dose-Response Relationship, Drug Alleles bcl-X Protein Embryo, Mammalian Myeloid Cell Leukemia Sequence 1 Protein |
Rights: | © 2012 by The American Society of Hematology |
DOI: | 10.1182/blood-2011-12-398834 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/575535 http://purl.org/au-research/grants/nhmrc/461219 http://purl.org/au-research/grants/nhmrc/361646 |
Published version: | http://dx.doi.org/10.1182/blood-2011-12-398834 |
Appears in Collections: | Aurora harvest 4 Medicine publications |
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