ESH Erythro 2025 | The impact of ineffective erythropoiesis in hemoglobinopathies & underlying mechanisms

Ineffective erythropoiesis has been very well characterized in beta-thalassemia, and it is one of the major phenomena happening in this disease. Nevertheless, very recently, we have shown that ineffective erythropoiesis is also happening in sickle cell disease, and it is characterized by high levels of apoptosis in the terminal erythroid differentiation phase. We need to keep in mind that the ineffective erythropoiesis present in sickle cell disease is not as high as what is happening in beta-thalassemia. Even though both of these diseases are hemoglobinopathies, the presence and the impact of ineffective erythropoiesis is different. In sickle cell disease, we have a phenomenon that is known as defective erythropoiesis, which happens when there is a disruption in the skewing between the myeloid and the erythroid lineage. And this is something that we see in sickle cell and not in thalassemia. So very recently, I have shown that ineffective erythropoiesis in sickle cell is characterized by a decrease in GATA1. GATA1 is the main transcription factor responsible for erythropoiesis. And so when its levels are decreased, this has a major impact on the process and on the outcome of red cells. And so increasing GATA1 levels could be one of the therapeutic targets that we can imagine for sickle cell disease and also for other pathologies. This has been tested, for example, in tPA, and we can really imagine this kind of therapy for sickle. But we have to keep in mind that in sickle cell disease, the main axis of the therapy should be to decrease the sickle hemoglobin in the patient because only by increasing, for example, fetal hemoglobin, we can ameliorate the disease pathology in the patients and decrease the complications. So even if we give the treatment to ameliorate ineffective erythropoiesis, we need to keep in mind that this could require a combination treatment with other molecules that aim to play a role in increasing fetal hemoglobin.

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