Bcl-xL, platelets and megakaryopoiesis

Platelets are small anucleate blood cells playing an essential role in blood clotting. In human, their average life span is 10 days, and their physiological amount is between 150 000 and 400 000/µL. Platelets are a unique model in terms of life span regulation because they only depend on 2 antagonist Bcl-2 family members: Bcl-xL for their survival, and Bak for their death. Platelets survive as long as pro-apoptotic Bak is kept inactive by interaction with Bcl-xL (Josefsson and James, JEM, 2011). Concurrently, Bcl-xL genetic ablation or pharmacological inhibition results in severe thrombocytopenia.

How Bak/Bcl-xL interaction is released to terminate platelet life is still unsolved, as all the hypotheses tested so far (a shorter life span of Bcl-xL compared to Bak for example) have been invalidated. Together with Muriel Priault (IBGC, CNRS UMR5095, Bordeaux), expert in biochemistry, specialized in Bcl-xL, we have previously shown that Bcl-xL undergoes sequential post-translational modifications with time. This process is akin to a molecular aging. We now aim to determine whether this phenomenon is merely a platelet age marker, or whether it actually causes Bcl-xL dysfunction and consequent platelet death. In parallel, we will use the sequential modifications undergone by Bcl-xL to screen new compounds capable of delaying this molecular aging. Identifying such compounds will open the possibility to extend Bcl-xL functionality for a longer time in platelets, which will translate into a protracted life span of platelets in platelet concentrates, thus extending their shelf-life.

We previously demonstrated that some acquired chronic thrombocytopenias are not due to an immune disorder, but rather are acquired hematological diseases characterized by a pure defect in platelet production (Riviere, BJH, 2015). Indeed, we describe a defect of proplatelet formation by megakaryocytes. We named these thrombocytopenias idiopathic chronic thrombocytopenia of undetermined significance (ICTUS). Together with the team of William Vainchenker (Inserm UMR1170, Villejuif), we hypothesize that ICTUS is a form of clonal hematopoiesis of indeterminate potential (CHIP) in the majority of cases. Given the role of Bcl-xL in proplatelet formation in mice, we hypothesize that ICTUS are related to a Bcl-xL downregulation in megakaryocytes and platelets. We now aim to precisely identify ICTUS and the mechanism of the thrombocytopenia, and facilitate its diagnosis by developing biomarkers. We got an ANR funding for this project: ANR- 18-CE17-0011-02.