BCL-2 is dispensable for thrombopoiesis and platelet survival

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Debrincat, MA; Pleines, I; Lebois, M; Lane, RM; Holmes, ML; Corbin, J; Vandenberg, CJ; Alexander, WS; Ng, AP; Strasser, A; ...Date
2015-04-01Source Title
Cell Death and DiseasePublisher
NATURE PUBLISHING GROUPUniversity of Melbourne Author/s
Josefsson, Emma; Kile, Benjamin; Strasser, Andreas; Ng, Ashley; Vandenberg, Cassandra; Bouillet, Philippe; Alexander, Warren; DEBRINCAT, MARLYSE ANNE; PLEINES, IRINAAffiliation
Medical Biology (W.E.H.I.)School of BioSciences
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Debrincat, M. A., Pleines, I., Lebois, M., Lane, R. M., Holmes, M. L., Corbin, J., Vandenberg, C. J., Alexander, W. S., Ng, A. P., Strasser, A., Bouillet, P., Sola-Visner, M., Kile, B. T. & Josefsson, E. C. (2015). BCL-2 is dispensable for thrombopoiesis and platelet survival. CELL DEATH & DISEASE, 6 (4), https://doi.org/10.1038/cddis.2015.97.Access Status
Open AccessAbstract
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.
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