Mcl-1 and Bcl-xL coordinately regulate megakaryocyte survival
Copyright policy )Mcl-1 and Bcl-xL coordinately regulate megakaryocyte survival
Abstract Mature megakaryocytes depend on the function of Bcl-xL, a member of the Bcl-2 family of prosurvival proteins, to proceed safely through the process of platelet shedding. Despite this, loss of Bcl-xL 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-1Pf4Δ/Pf4Δ animals. However, treatment with ABT-737, a BH3 mimetic compound that inhibits the prosurvival proteins Bcl-2, Bcl-xL, and Bcl-w resulted in the complete ablation of megakaryocytes and platelets. Genetic deletion of both Mcl-1 and Bcl-xL in megakaryocytes resulted in preweaning lethality. Megakaryopoiesis in Bcl-xPf4Δ/Pf4ΔMcl-1Pf4Δ/Pf4Δ embryos was severely compromised, and these animals exhibited ectopic bleeding. Our studies indicate that the combination of Bcl-xL and Mcl-1 is essential for the viability of the megakaryocyte lineage.
- Peter MacCallum Cancer Centre Australia
- University of South Australia Australia
- Centre for Cancer Biology Australia
- University of Melbourne Australia
- Walter and Eliza Hall Institute of Medical Research Australia
Blood Platelets, family, Cell Survival, bcl-2, bcl-X Protein, Cell Count, Hemorrhage, Inbred C57BL, hematopoietic stem-cells, in-vivo, Piperazines, Thrombopoiesis, Nitrophenols, Dose-Response Relationship, Mice, Fetus, Animals, Alleles, Cell Size, Lymphatic Vessels, Sulfonamides, bone-marrow, Cell Death, Dose-Response Relationship, Drug, Mammalian, Biphenyl Compounds, blood-platelets, apoptosis, Embryo, Mammalian, Blood Cell Count, inhibitor, Mice, Inbred C57BL, idiopathic thrombocytopenic purpura, Proto-Oncogene Proteins c-bcl-2, Liver, Organ Specificity, Embryo, Myeloid Cell Leukemia Sequence 1 Protein, Drug, Megakaryocytes, platelet senescence, Gene Deletion
Blood Platelets, family, Cell Survival, bcl-2, bcl-X Protein, Cell Count, Hemorrhage, Inbred C57BL, hematopoietic stem-cells, in-vivo, Piperazines, Thrombopoiesis, Nitrophenols, Dose-Response Relationship, Mice, Fetus, Animals, Alleles, Cell Size, Lymphatic Vessels, Sulfonamides, bone-marrow, Cell Death, Dose-Response Relationship, Drug, Mammalian, Biphenyl Compounds, blood-platelets, apoptosis, Embryo, Mammalian, Blood Cell Count, inhibitor, Mice, Inbred C57BL, idiopathic thrombocytopenic purpura, Proto-Oncogene Proteins c-bcl-2, Liver, Organ Specificity, Embryo, Myeloid Cell Leukemia Sequence 1 Protein, Drug, Megakaryocytes, platelet senescence, Gene Deletion
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