title: BCL-2 is dispensable for thrombopoiesis and platelet survival.
abstract: Navitoclax (ABT-263), an inhibitor of the pro-survival BCL-2 family proteins BCL-2, BCL-XL and BCL-W, has shown clinical efficacy in certain BCL-2-dependent haematological cancers, but causes dose-limiting thrombocytopaenia. The latter effect is caused by Navitoclax directly inducing the apoptotic death of platelets, which are dependent on BCL-XL for survival. Recently, ABT-199, a selective BCL-2 antagonist, was developed. It has shown promising anti-leukaemia activity in patients whilst sparing platelets, suggesting that the megakaryocyte lineage does not require BCL-2. In order to elucidate the role of BCL-2 in megakaryocyte and platelet survival, we generated mice with a lineage-specific deletion of Bcl2, alone or in combination with loss of Mcl1 or Bclx. Platelet production and platelet survival were analysed. Additionally, we made use of BH3 mimetics that selectively inhibit BCL-2 or BCL-XL. We show that the deletion of BCL-2, on its own or in concert with MCL-1, does not affect platelet production or platelet lifespan. Thrombocytopaenia in Bclx-deficient mice was not affected by additional genetic loss or pharmacological inhibition of BCL-2. Thus, BCL-2 is dispensable for thrombopoiesis and platelet survival in mice.
authors.affiliation: 1] The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, Australia [2] Department of Medical Biology, The University of Melbourne, 1G Royal Parade, Parkville, VIC, Australia.
authors.forename: M A
authors.initials: MA
authors.lastname: Debrincat
authors.affiliation: 1] The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, Australia [2] Department of Medical Biology, The University of Melbourne, 1G Royal Parade, Parkville, VIC, Australia.
authors.forename: I
authors.initials: I
authors.lastname: Pleines
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Lebois
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, Australia.
authors.forename: R M
authors.initials: RM
authors.lastname: Lane
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, Australia.
authors.forename: M L
authors.initials: ML
authors.lastname: Holmes
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Corbin
authors.affiliation: 1] The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, Australia [2] Department of Medical Biology, The University of Melbourne, 1G Royal Parade, Parkville, VIC, Australia.
authors.forename: C J
authors.initials: CJ
authors.lastname: Vandenberg
authors.affiliation: 1] The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, Australia [2] Department of Medical Biology, The University of Melbourne, 1G Royal Parade, Parkville, VIC, Australia.
authors.forename: W S
authors.initials: WS
authors.lastname: Alexander
authors.affiliation: 1] The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, Australia [2] Department of Medical Biology, The University of Melbourne, 1G Royal Parade, Parkville, VIC, Australia.
authors.forename: A P
authors.initials: AP
authors.lastname: Ng
authors.affiliation: 1] The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, Australia [2] Department of Medical Biology, The University of Melbourne, 1G Royal Parade, Parkville, VIC, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Strasser
authors.affiliation: 1] The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, Australia [2] Department of Medical Biology, The University of Melbourne, 1G Royal Parade, Parkville, VIC, Australia.
authors.forename: P
authors.initials: P
authors.lastname: Bouillet
authors.affiliation: Boston Children's Hospital, Division of Newborn Medicine, Boston, MA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Sola-Visner
authors.affiliation: 1] The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, Australia [2] Department of Medical Biology, The University of Melbourne, 1G Royal Parade, Parkville, VIC, Australia.
authors.forename: B T
authors.initials: BT
authors.lastname: Kile
authors.affiliation: 1] The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, Australia [2] Department of Medical Biology, The University of Melbourne, 1G Royal Parade, Parkville, VIC, Australia.
authors.forename: E C
authors.initials: EC
authors.lastname: Josefsson
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000166:cytology* / Q000473:pathology; D002470:Cell Survival / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000172:deficiency*; D013921:Thrombocytopenia / Q000097:blood / Q000473:pathology; D034061:Thrombopoiesis / Q000502:physiology*; D051020:bcl-X Protein / Q000172:deficiency
chemical_list: C494812:Bcl2l1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; C052617:Bcl2 protein, mouse