Ineffective erythropoiesis (IE) is an important factor in many types of anemias. Recently, a study by El Hoss et al provided compelling evidence for IE being an important part of the pathophysiology of sickle cell anemia (SCA). Furthermore, we developed a clinical index to measure IE and showed that patients with the SS genotype had increased IE compared to healthy donors (HD). However, the molecular mechanisms of IE in SCA, its relationship todisease heterogeneity and its potential as a therapeutic target, remain unknown.  Importantly, GATA1, an essential erythroid transcription factor known to be downregulated in haematological conditions presenting with IE, has not been previously investigated in SCA. Therefore, the aim of our work is to elucidate the role of GATA-1 in IE of SCA. By performing ex-vivo differentiation of primary human SS CD34+ cells we revealed (i) a significant delay in differentiation (ii) an elevated level of oxidative stress and a reduction in GATA-1 protein levels. In a parallel line of evidence, IE manifested in SS mice and was characterized by increased oxidative stress levels in both the bone marrow and spleen tissues. Moreover, both tissues showed a significant decline in GATA-1 levels. This research seeks to provide novel insights into the role of GATA-1 in sickle erythropoiesis, the latter could guide the development of potential therapeutic strategies targeting GATA-1 and thus improving the bone marrow niche and erythropoiesis in SCA.

Invitation by Catherine Lavazec and Michaela Fontenay.