TGF-Beta Signaling And Ineffective Erythropoiesis Of Beta-Thalassemia – TIEBET

We, and others recently discovered that GDF11, a TGF-ß superfamily member, acts as an autocrine potent inhibitor of erythropoiesis by blocking terminal differentiation of red cell progenitors, by yet unexplained mechanism. Interestingly, we showed that GDF11 was increased in splenic erythroblasts from thalassemic mice and in erythroblasts and sera from subjects with beta-thalassemia, thereby contributing to the ineffective erythropoiesis phenotype characterizing this genetic disorder. Surprisingly, this is in sharp contrast with our earlier observations that another ligand of this superfamily, TGF-ß1, acts as a strong inducer of terminal differentiation by blocking cell cycle and promoting red blood cell maturation. The molecular bases underpinning the opposite effects of GDF11/TGF-ß1 on erythropoiesis are currently unknown. Deriving from our previous work, ongoing clinical trials led by us demonstrate that the activin type IIA receptor fusion proteins act as potent suppressors of GDF11 signaling in vivo, significantly improve ineffective erythropoiesis, increase hemoglobin levels in non-transfusion-dependent beta-thalassemia patients (= 1.0 g/dL) and significantly reduces transfusion burden on transfusion-dependent beta-thalassemia patients. Taken altogether this shows that aberrant GDF11 signaling is a key feature of beta-thalassemia, and that this pathway is an attractive therapeutic target to correct ineffective erythropoiesis in clinical settings. However, the exact molecular mechanisms of GDF-11 synthesis and consequences of GDF11 signaling in erythropoiesis are unclear and it is not known why GDF11 and TGF-ß1, despite signaling apparently through the same effector molecules (i.e. SMAD2/3) result in opposite biological consequences in vivo (i.e. blocking versus inducing erythroid progenitors differentiation, respectively). The aim of this proposal is to shed light on the molecular mechanisms triggered by GDF11 and TGF-ß1 in erythroid differentiation in vivo. We will undertake an integrative approach combining animal models and high throughput assays to characterize the molecular pathways and transcription factors involved in the differential effects of TGF-ß1 and GDF11 in both normal and ineffective erythropoiesis of beta-thalassemia, which have clear clinical and therapeutic relevance.