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β-Thalassemia and Polycythemia vera: targeting chronic stress erythropoiesis - PubMed

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Review

β-Thalassemia and Polycythemia vera: targeting chronic stress erythropoiesis

Bart J Crielaard et al. Int J Biochem Cell Biol. 2014 Jun.

Erratum in

  • Int J Biochem Cell Biol. 2014 Oct;55:349

Abstract

β-Thalassemia and Polycythemia vera are genetic disorders which affect the synthesis of red blood cells, also referred to as erythropoiesis. Although essentially different in clinical presentation - patients with β-thalassemia have an impairment in β-globin synthesis leading to defective erythrocytes and anemia, while patients with Polycythemia vera present with high hemoglobin levels because of excessive red blood cell synthesis - both pathologies may characterized by lasting high erythropoietic activity, i.e. chronic stress erythropoiesis. In both diseases, therapeutic strategies targeting chronic stress erythropoiesis may improve the address phenotype and prevent secondary pathology, such as iron overload. The current review will address the basic concepts of these strategies to reduce chronic stress erythropoiesis, which may have significant clinical implications in the near future.

Keywords: Chronic stress erythropoiesis; Iron metabolism; Macrophages; Polycythemia vera; β-Thalassemia.

Copyright © 2014 Elsevier Ltd. All rights reserved.

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Figures

Figure 1
Figure 1

Cellular mechanisms regulating steady-state and (chronic) stress erythropoiesis. In steady-state erythropoiesis, erythroid proliferation, differentiation and survival is primarily dependent on EpoR/Jak2/Stat5 signaling and iron-dependent IRE/IRP modulation (A). In (chronic) stress erythropoiesis, the expansion of stress erythroid progenitors is regulated by several other mechanisms in addition to the EpoR/Jak2/Stat5 pathway. This includes BMP4 signaling through SMAD4 and SCF/c-kit signaling through Akt/Erk, which are both dependent on oxygenation, possibly via HIFs; pIgA1-mediated transferrin receptor 1 (TfR1) activation which stimulates Akt/Erk and potentiates EpoR/Stat5 signaling; glucocorticoid receptor (GR) signaling via ZFP36L2; and the desert Hedgehog (Dhh) pathway, which inhibits the response. Moreover, there is a regulating role of the microenvironment through Notch2 signaling, which stimulates switching of early progenitors towards the erythroid lineage, as well as macrophage-associated regulation, which stimulate erythropoiesis through a currently unknown mechanism (B).

Figure 1
Figure 1

Cellular mechanisms regulating steady-state and (chronic) stress erythropoiesis. In steady-state erythropoiesis, erythroid proliferation, differentiation and survival is primarily dependent on EpoR/Jak2/Stat5 signaling and iron-dependent IRE/IRP modulation (A). In (chronic) stress erythropoiesis, the expansion of stress erythroid progenitors is regulated by several other mechanisms in addition to the EpoR/Jak2/Stat5 pathway. This includes BMP4 signaling through SMAD4 and SCF/c-kit signaling through Akt/Erk, which are both dependent on oxygenation, possibly via HIFs; pIgA1-mediated transferrin receptor 1 (TfR1) activation which stimulates Akt/Erk and potentiates EpoR/Stat5 signaling; glucocorticoid receptor (GR) signaling via ZFP36L2; and the desert Hedgehog (Dhh) pathway, which inhibits the response. Moreover, there is a regulating role of the microenvironment through Notch2 signaling, which stimulates switching of early progenitors towards the erythroid lineage, as well as macrophage-associated regulation, which stimulate erythropoiesis through a currently unknown mechanism (B).

Figure 2
Figure 2

Disease characteristics of β-thalassemia and Polycythemia and the effect of reducing chronic stress erythropoiesis. β-thalassemia is characterized by a defect in β-globin synthesis, leading to the formation in imperfect erythrocytes with reduced oxygen carrying ability and short lifespan. As a result, patients have anemia, splenomegaly, and iron overload due to increased iron absorption. Therapy consists of blood transfusions, which may aggravate iron overload even further. Polycythemia vera is caused by a defect in Jak2 signaling, resulting in excessive erythrocyte production, causing erythrocytosis and splenomegaly. Therapy includes phlebotomies to reduce hematocrit and prevent secondary complications. In both disorders reduction of chronic stress erythropoiesis improves the pathological phenotype, leading to reduction of anemia, splenomegaly and iron overload in case of β-thalassemia, and reduction of hematocrit and splenomegaly in case Polycythemia vera. As a consequence, the frequency of therapeutic interventions may be reduced.

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