Mcl-1 and Bcl-xL coordinately regulate megakaryocyte survival Academic Article uri icon

abstract

  • 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.

authors

  • Debrincat, Marlyse A
  • Josefsson, Emma C
  • James, Chloé
  • Henley, Katya J
  • Ellis, Sarah
  • Lebois, Marion
  • Betterman, Kelly L
  • Lane, Rachael M
  • Rogers, Kelly L
  • White, Michael J
  • Roberts, Andrew W
  • Harvey, Natasha L
  • Metcalf, Donald
  • Kile, Benjamin T

publication date

  • June 14, 2012

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