β-Thalassemia intermedia and major are characterized by ineffective erythropoiesis (IE), requiring sporadic or chronic blood transfusions, respectively. Some of the major consequences of IE are extra-medullary hematopoiesis (EMH), splenomegaly and systemic iron overload mediated by transfusion therapy and down-regulation of hepcidin. Using mouse models of β-thalassemia intermedia (th3/+) and major (th3/th3), and human specimens we investigated IE in this disorder. Th3/+ and th3/th3 erythroid cells were analyzed with respect to rates of apoptosis and degrees of cell proliferation and differentiation. We found that there was both a relative and absolute expansion of the immature erythroid progenitor cell fraction in thalassemic mice compared to cells in the final stages of differentiation. Further investigation of the thalassemic erythroid cells in vivo and in vitro indicated that a larger number of the thalassemic cells are associated with the phosphorylated form of the Jak2 protein kinase than in normal mice. In fact, their proliferation was prevented by TG101209, a Jak2 inhibitor. Similar compounds are currently utilized or being considered for use in the treatment of myeloproliferative diseases such as polycythemia vera. In order to assess the potential of Jak2 inhibitors in limiting IE in β-thalassemia, we administered TG101209 to th3/+ mice. We found that both 10 and 18 days of treatment were sufficient to dramatically reduce the spleen size and the percentage of immature erythroid progenitors therein compared with administration of a placebo. However, these changes were associated with decreasing hemoglobin levels (
Disclosures: No relevant conflicts of interest to declare.