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Blood, 1 August 2008, Vol. 112, No. 3, pp. 875-885.
Prepublished online as a Blood First Edition Paper on May 14, 2008; DOI 10.1182/blood-2007-12-126938.
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Submitted December 19, 2007
Accepted April 16, 2008
Decreased differentiation of erythroid cells exacerbates ineffective erythropoiesis in  -thalassemia
Ilaria V Libani, Ella C Guy, Luca Melchiori, Raffaella Schiro, Pedro Ramos, Laura Breda, Thomas Scholzen, Amy Chadburn, YiFang Liu, Margrit Kernbach, Bettina Baron-Luehr, Matteo Porotto, Maria de Sousa, Eliezer A Rachmilewitz, John D Hood, M. Domenica Cappellini, Patricia J Giardina, Robert W Grady, Johannes Gerdes, and Stefano Rivella*
Department of Pediatric Hematology-Oncology, Children's Cancer and Blood Foundation Laboratories, Weill Medical College of Cornell University, New York, New York, United States
Iron Genes and Immune System (IRIS Lab), IBMC Instituto de Biologia Molecular e Celular, Oporto University, Oporto, Portugal
Department of Immunology and Cell Biology, Division of Tumour Biology, Research Center Borstel, Borstel, Germany
Department of Pathology and Laboratory of Medicine, Weill Medical College of Cornell University, New York, New York, United States
Department of Pediatrics and of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York, United States
Institute of Hematology, E. Wolfson Medical Centre, Holon, Israel
Research, TargeGen, Inc, San Diego, California, United States
Centro Anemie Congenite, Ospedale Maggiore Policlinico, IRCCS, University of Milan, Milan, Italy
* Corresponding author; email: str2010{at}med.cornell.edu.
In  -thalassemia, the mechanism driving ineffective erythropoiesis (IE) is insufficiently understood. We analyzed mice affected by -thalassemia and observed, unexpectedly, a relatively small increase in apoptosis of their erythroid cells compared to normal mice. Therefore, we sought to determine if 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, Ki-67 and the anti-apoptotic protein Bcl-XL. They also differentiated less that normal erythroid ones in vitro. In order to investigate whether Jak2 could be responsible for the limited cell differentiation, we administered a Jak2 inhibitor, TG101209, to normal and thalassemic mice. Exposure to TG101209 dramatically decreased the spleen size but also affected anemia. While 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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