title: Mcl-1 and Bcl-x(L) coordinately regulate megakaryocyte survival.
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(Pf4Δ/Pf4Δ) 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(Pf4Δ/Pf4Δ) Mcl-1(Pf4Δ/Pf4Δ) 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.
authors.affiliation: Cancer and Hematology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
authors.forename: Marlyse A
authors.initials: MA
authors.lastname: Debrincat
authors.forename: Emma C
authors.initials: EC
authors.lastname: Josefsson
authors.forename: Chloé
authors.initials: C
authors.lastname: James
authors.forename: Katya J
authors.initials: KJ
authors.lastname: Henley
authors.forename: Sarah
authors.initials: S
authors.lastname: Ellis
authors.forename: Marion
authors.initials: M
authors.lastname: Lebois
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Betterman
authors.forename: Rachael M
authors.initials: RM
authors.lastname: Lane
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Rogers
authors.forename: Michael J
authors.initials: MJ
authors.lastname: White
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Roberts
authors.forename: Natasha L
authors.initials: NL
authors.lastname: Harvey
authors.forename: Donald
authors.initials: D
authors.lastname: Metcalf
authors.forename: Benjamin T
authors.initials: BT
authors.lastname: Kile
mesh_terms: D000483:Alleles; D000818:Animals; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000494:pharmacology; D001772:Blood Cell Count; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002452:Cell Count; D016923:Cell Death / Q000187:drug effects; D048429:Cell Size; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian / Q000187:drug effects / Q000473:pathology; D005333:Fetus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017353:Gene Deletion; D006470:Hemorrhage / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D042601:Lymphatic Vessels / Q000187:drug effects / Q000473:pathology; D008533:Megakaryocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols / Q000008:administration & dosage / Q000494:pharmacology; D009928:Organ Specificity / Q000187:drug effects; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000172:deficiency / Q000378:metabolism*; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology; D034061:Thrombopoiesis / Q000187:drug effects; D051020:bcl-X Protein / Q000378:metabolism*
chemical_list: C501332:ABT-737; D001713:Biphenyl Compounds; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D051020:bcl-X Protein