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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alleles
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Animals
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Biphenyl Compounds / administration & dosage
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Biphenyl Compounds / pharmacology
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Blood Cell Count
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Blood Platelets / drug effects
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Blood Platelets / metabolism
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Blood Platelets / pathology
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Cell Count
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Cell Death / drug effects
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Cell Size
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Cell Survival / drug effects
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Dose-Response Relationship, Drug
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Embryo, Mammalian / drug effects
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Embryo, Mammalian / pathology
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Fetus / drug effects
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Fetus / metabolism
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Fetus / pathology
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Gene Deletion
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Hemorrhage / pathology
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Liver / drug effects
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Liver / embryology
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Liver / metabolism
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Liver / pathology
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Lymphatic Vessels / drug effects
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Lymphatic Vessels / pathology
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Megakaryocytes / drug effects
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Megakaryocytes / metabolism*
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Megakaryocytes / pathology*
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Megakaryocytes / ultrastructure
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Mice
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Mice, Inbred C57BL
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Myeloid Cell Leukemia Sequence 1 Protein
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Nitrophenols / administration & dosage
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Nitrophenols / pharmacology
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Organ Specificity / drug effects
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Piperazines / administration & dosage
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Piperazines / pharmacology
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Proto-Oncogene Proteins c-bcl-2 / deficiency
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Proto-Oncogene Proteins c-bcl-2 / metabolism*
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Sulfonamides / administration & dosage
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Sulfonamides / pharmacology
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Thrombopoiesis / drug effects
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bcl-X Protein / metabolism*
Substances
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ABT-737
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Biphenyl Compounds
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Mcl1 protein, mouse
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Myeloid Cell Leukemia Sequence 1 Protein
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Nitrophenols
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Piperazines
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Proto-Oncogene Proteins c-bcl-2
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Sulfonamides
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bcl-X Protein