Mcl-1 and Bcl-x L coordinately regulate megakaryocyte survival

Marlyse A. Debrincat, Emma C. Josefsson, Chloe 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, Benjamin T. Kile

Research output: Contribution to journalArticleResearchpeer-review

54 Citations (Scopus)

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/Pf4Δ Mcl-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.

Original languageEnglish
Pages (from-to)5850-5858
Number of pages9
JournalBlood
Volume119
Issue number24
DOIs
Publication statusPublished - 14 Jun 2012
Externally publishedYes

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