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https://hdl.handle.net/2440/123606
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Type: | Journal article |
Title: | BCL-2 is dispensable for thrombopoiesis and platelet survival |
Author: | 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. |
Citation: | Cell Death and Disease, 2015; 6(4):e1721-1-e1721-8 |
Publisher: | Nature Publishing Group |
Issue Date: | 2015 |
ISSN: | 2041-4889 2041-4889 |
Statement of Responsibility: | M A Debrincat, I Pleines, M Lebois, R M Lane, M L Holmes ... B T Kile ... et al. |
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. |
Keywords: | Blood Platelets Animals Mice, Transgenic Mice Thrombocytopenia Proto-Oncogene Proteins c-bcl-2 Thrombopoiesis Cell Survival bcl-X Protein |
Rights: | © 2015 Macmillan Publishers Limited All rights reserved |
DOI: | 10.1038/cddis.2015.97 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/575535 http://purl.org/au-research/grants/nhmrc/1079250 http://purl.org/au-research/grants/nhmrc/1060179 http://purl.org/au-research/grants/nhmrc/1016647 http://purl.org/au-research/grants/nhmrc/1016701 http://purl.org/au-research/grants/nhmrc/1063008 http://purl.org/au-research/grants/nhmrc/1058344 http://purl.org/au-research/grants/nhmrc/1020363 http://purl.org/au-research/grants/nhmrc/361646 |
Published version: | http://dx.doi.org/10.1038/cddis.2015.97 |
Appears in Collections: | Aurora harvest 8 Medicine publications |
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