Mcl-1 and Bcl-x(L) coordinately regulate megakaryocyte survival
- Author(s)
- Debrincat, MA; Josefsson, EC; James, C; Henley, KJ; Ellis, S; Lebois, M; Betterman, KL; Lane, RM; Rogers, KL; White, MJ; Roberts, AW; Harvey, NL; Metcalf, D; Kile, BT;
- 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
- Research Division(s)
- Cancer And Haematology
- Publisher's Version
- https://doi.org/10.1182/blood-2011-12-398834
- Terms of Use/Rights Notice
- © 2012 by The American Society of Hematology
Creation Date: 2012-06-14 12:00:00