Mcl-1 and Bcl-x(L) coordinately regulate megakaryocyte survival
Details
Publication Year 2012-06-14, Volume 119, Issue #24, Page 5850-5858
Journal Title
BLOOD
Publication Type
Journal Article
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(Pf4 Delta/Pf4 Delta) 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(Pf4 Delta/Pf4 Delta) Mcl-1(Pf4 Delta/Pf4 Delta) 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. (Blood. 2012; 119(24):5850-5858)
Publisher
AMER SOC HEMATOLOGY
Keywords
IDIOPATHIC THROMBOCYTOPENIC PURPURA; HEMATOPOIETIC STEM-CELLS; BONE-MARROW; IN-VIVO; PLATELET SENESCENCE; BLOOD-PLATELETS; BCL-2; INHIBITOR; APOPTOSIS; FAMILY
WEHI Research Division(s)
Cancer And Haematology
Rights Notice
© 2012 by The American Society of Hematology


Creation Date: 2012-06-14 12:00:00
Last Modified: 0001-01-01 12:00:00
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