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.
Highlights
In platelets, BCL-XL is the critical pro-survival BCL-2 family member required to keep BAK and BAX in check
Mice lacking BCL-2 in the megakaryocytic lineage were generated by crossing animals carrying a floxed allele of Bcl[222] with Pf4-Cre transgenic animals.[23]
It has been previously reported that in cultured primary mouse megakaryocytes, deletion of Bcl-x or treatment with ABT-737 triggers loss of cell viability, Caspase-3/7 activity and a failure of proplatelet formation.[5]. In line with these data, we found that the BCL-XL-selective inhibitor A-463 induced dosedependent Caspase-3/7 activation in wild-type foetal liverderived megakaryocytes (Figure 5a)
Summary
BCL-XL is the critical pro-survival BCL-2 family member required to keep BAK and BAX in check. BCL-2 and BCL-W) triggers BAK/BAX-mediated platelet apoptosis.[9,10,11] As a result, these drugs cause dosedependent thrombocytopaenia in mice, dogs and humans.[9,11,12,13,14] thrombocytopaenia is the doselimiting toxicity for Navitoclax.[12,13,14] This fact provided additional impetus for the development of agents that target BCL-2, beginning with ABT-199,15 a BCL-2-selective antagonist currently in clinical trials for the treatment of a range of haematological malignancies including chronic lymphocytic leukaemia, non-Hodgkin’s lymphoma, follicular lymphoma, mantle cell lymphoma, multiple myeloma and acute myeloid leukaemia. Consistent with the genetic studies, administration of ABT-737 to Mcl1Pf4Δ/Pf4Δ mice, which lack MCL-1 in megakaryocytes and platelets, induces acute, fulminant BAK/BAX-
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