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Review
. 2009 May;16(3):187-94.
doi: 10.1097/MOH.0b013e32832990a4.

Ineffective erythropoiesis and thalassemias

Stefano Rivella  1
Affiliations
Review

Ineffective erythropoiesis and thalassemias

Stefano Rivella. Curr Opin Hematol. 2009 May.

Abstract

Purpose of review: In thalassemia, ineffective erythropoiesis is characterized by apoptosis of the maturing nucleated erythroid cells. New studies also suggest that limited erythroid cell differentiation plays a role in the development of ineffective erythropoiesis. This would further exacerbate anemia and increase iron absorption.

Recent findings: During erythroid differentiation and maturation, it is critical that the components of hemoglobin are made in stoichiometric amounts. It is, therefore, conceivable that factors that modify this process intrinsically or extrinsically will also affect erythropoiesis. Several proteins have the potential to alter erythroid replication and differentiation in conditions of ineffective erythropoiesis. Elevated erythropoietin levels increase the number of erythroid precursors bearing a phosphorylated form of Jak2. This, in a pathological condition, may contribute to limited erythroid differentiation. Unbalanced synthesis of globins and heme modifies the activity of the heme-regulated inhibitor kinase, affecting proliferation and differentiation of the erythroid precursors. In addition, inefficient elimination of reactive oxygen species, which are increased under conditions of iron overload, may also hamper erythropoiesis.

Summary: Use of Jak2 inhibitors may limit the overproduction of immature erythroid cells in thalassemia, with the potential of reversing extramedullary hematopoiesis and preventing splenectomy. In addition, preventing iron overload and formation of reactive oxygen species may also be beneficial in limiting tissue damage and ineffective erythropoiesis.

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Figures

Figure 1
Figure 1
Pleiotropic effects observed in thalassemia
Figure 2
Figure 2
Relationship between hepcidin and iron content in the liver and spleen in th3/+ mice over time
Figure 3
Figure 3
Potential causes that limit erythroid differentiation in thalassemia
Figure 4
Figure 4
Potential correlation between Jak2 and ineffective erythropoiesis
See this image and copyright information in PMC

References

    1. Han AP, Fleming MD, Chen JJ. Heme-regulated eIF2alpha kinase modifies the phenotypic severity of murine models of erythropoietic protoporphyria and beta-thalassemia. J Clin Invest. 2005;115:1562–1570. - PMC - PubMed

    1. Chen JJ. Regulation of protein synthesis by the heme-regulated eIF2alpha kinase: relevance to anemias. Blood. 2007;109:2693–2699. Heme-regulated translation mediated by the HRI provides one major mechanism that ensures balanced synthesis of globins and heme. Translational regulation by HRI is critical to reduce excess synthesis of globin proteins or heme in thalassemia and other hemoglobinopathies and thus reduces the severity of these diseases.

    1. Marinkovic D, Zhang X, Yalcin S, et al. Foxo3 is required for the regulation of oxidative stress in erythropoiesis. J Clin Invest. 2007;117:2133–2144. The FoxO3 member of the FoxO family of transcription factors is essential to prevent overaccumulation of ROS. In the absence of FoxO3, erythrocytes exhibited decreased expression of ROS-scavenging enzymes and had a ROS-mediated shortened lifespan and evidence of oxidative damage.

    1. Libani IV, Guy EC, Melchiori L, et al. Decreased differentiation of erythroid cells exacerbates ineffective erythropoiesis in beta-thalassemia. Blood. 2008;112:875–885. This study introduced the notion that decreased erythroid cell differentiation contributes to ineffective erythropoiesis, exacerbating anemia. To some extent, this is mediated by Jak2. This observation may have important consequences as the use of Jak2 inhibitors has the potential to offer an alternative to splenectomy and profoundly change the management of this disorder.

    1. Steinberg MH, Forget BG, Higgs DR, et al. Disorders of hemoglobin: genetics, pathophysiology and clinical management. Cam- bridge University Press; Cambridge, UK: 2001.

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