What can we learn from ineffective erythropoiesis in thalassemia?

Abstract

Erythropoiesis is a dynamic process regulated at multiple levels to balance proliferation, differentiation and survival of erythroid progenitors. Ineffective erythropoiesis is a key feature of various diseases, including β-thalassemia. The pathogenic mechanisms leading to ineffective erythropoiesis are complex and still not fully understood. Altered survival and decreased differentiation of erythroid progenitors are both critical processes contributing to reduced production of mature red blood cells. Recent studies have identified novel important players and provided major advances in the development of targeted therapeutic approaches. In this review, β-thalassemia is used as a paradigmatic example to describe our current knowledge on the mechanisms leading to ineffective erythropoiesis and novel treatments that may have the potential to improve the clinical phenotype of associated diseases in the future.

Fyn kinase is a novel modulator of erythropoietin signaling and stress erythropoiesis

“…As shown in Figure 4F, Previous studies have shown that perturbation of autophagy is detrimental for erythroid maturation and has been documented in condition with disordered erythropoiesis such as β-thalassemic syndromes or chorea-acanthocytosis or during iron deficiency. 4,39 Consistent with this hypothesis, in Fyn −/− mouse erythroblasts we found accumulation of the autophagy cargo protein p62, a marker of autophagy inhibition. 4,39 Consistent with this hypothesis, in Fyn −/− mouse erythroblasts we found accumulation of the autophagy cargo protein p62, a marker of autophagy inhibition.…”

“…Erythroid differentiation is characterized by the production of reactive oxygen species (ROS) in response to erythropoietin (EPO) and by the large amount of iron imported into the cells for heme biosynthesis. [2][3][4][5] Previous studies have shown that the mice genetically lacking Lyn (Lyn −/− ) display reduced STAT5 activation and defective response to phenylhydrazine-(PHZ) induced stress erythropoiesis. EPO activates a signaling cascade, involving Jak2, as the primary kinase, and Lyn, a Tyr-kinase of the Src family (SFK), as secondary kinase.…”

“…1 During erythropoiesis, ROS could function as second messenger by modulating intracellular signaling pathways. [2][3][4] Fyn, is another member of the SFKs that is also expressed in hematopoietic cells. [2][3][4] These two kinases target STAT5 transcription factor, one of the key master transcription regulators involved in erythroid maturation events.…”

“…EPO activates a signaling cascade, involving Jak2, as the primary kinase, and Lyn, a Tyr-kinase of the Src family (SFK), as secondary kinase. [2][3][4] These two kinases target STAT5 transcription factor, one of the key master transcription regulators involved in erythroid maturation events. [2][3][4][5] Previous studies have shown that the mice genetically lacking Lyn (Lyn −/− ) display reduced STAT5 activation and defective response to phenylhydrazine-(PHZ) induced stress erythropoiesis.…”

“…[2][3][4] These two kinases target STAT5 transcription factor, one of the key master transcription regulators involved in erythroid maturation events. [2][3][4][5] Previous studies have shown that the mice genetically lacking Lyn (Lyn −/− ) display reduced STAT5 activation and defective response to phenylhydrazine-(PHZ) induced stress erythropoiesis. [2][3][4] Fyn, is another member of the SFKs that is also expressed in hematopoietic cells.…”