Ineffective erythropoiesis and thalassemias.
OBJECTIVE
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.


RESULTS
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.


CONCLUSIONS
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.
Rivella
Stefano
S
Department of Pediatric Hematology-Oncology, Children's Cancer and Blood Foundation Laboratories, Weill Medical College of Cornell University, New York, New York, USA. str2010@med.cornell.edu