Decreased differentiation of erythroid cells exacerbates ineffective erythropoiesis in beta-thalassemia |
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Authors: | Libani Ilaria V Guy Ella C Melchiori Luca Schiro Raffaella Ramos Pedro Breda Laura Scholzen Thomas Chadburn Amy Liu YiFang Kernbach Margrit Baron-Lühr Bettina Porotto Matteo de Sousa Maria Rachmilewitz Eliezer A Hood John D Cappellini M Domenica Giardina Patricia J Grady Robert W Gerdes Johannes Rivella Stefano |
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Institution: | 1 Department of Pediatric Hematology-Oncology, Children's Cancer and Blood Foundation Laboratories, Weill Medical College of Cornell University, New York, NY; 2 Centro Anemie Congenite, Fondazione Policlinico, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), University of Milan, Milan, Italy; 3 Iron Genes and Immune System (IRIS Lab), Instituto de Biologia Molecular e Celular (IBMC), Oporto University, Oporto, Portugal; 4 Research Center Borstel, Department of Immunology and Cell Biology, Division of Tumour Biology, Borstel, Germany; Departments of5 Pathology and Laboratory of Medicine and 6 Pediatrics and Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY; 7 E. Wolfson Medical Centre, Institute of Hematology, Holon, Israel; and 8 TargeGen, San Diego, CA |
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Abstract: | In β-thalassemia, the mechanism driving ineffective erythropoiesis (IE) is insufficiently understood. We analyzed mice affected by β-thalassemia and observed, unexpectedly, a relatively small increase in apoptosis of their erythroid cells compared with healthy mice. Therefore, we sought to determine whether IE could also be characterized by limited erythroid cell differentiation. In thalassemic mice, we observed that a greater than normal percentage of erythroid cells was in S-phase, exhibiting an erythroblast-like morphology. Thalassemic cells were associated with expression of cell cycle–promoting genes such as EpoR, Jak2, Cyclin-A, Cdk2, and Ki-67 and the antiapoptotic protein Bcl-XL. The cells also differentiated less than normal erythroid ones in vitro. To investigate whether Jak2 could be responsible for the limited cell differentiation, we administered a Jak2 inhibitor, TG101209, to healthy and thalassemic mice. Exposure to TG101209 dramatically decreased the spleen size but also affected anemia. Although our data do not exclude a role for apoptosis in IE, we propose that expansion of the erythroid pool followed by limited cell differentiation exacerbates IE in thalassemia. In addition, these results suggest that use of Jak2 inhibitors has the potential to profoundly change the management of this disorder. |
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