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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. This Article Full Text Full Text (PDF) Supplemental Methods and Figures All Versions of this Article: blood-2007-12-126938v1 112/3/875    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Libani, I. V. Articles by Rivella, S. PubMed PubMed Citation Articles by Libani, I. V. Articles by Rivella, S. Related Collections Red Cells Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  RED CELLS Decreased differentiation of erythroid cells exacerbates ineffective erythropoiesis in β-thalassemia Ilaria V. Libani1,2,*, Ella C. Guy1,*, Luca Melchiori1,*, Raffaella Schiro1,*, Pedro Ramos1,3, Laura Breda1, Thomas Scholzen4, Amy Chadburn5, YiFang Liu5, Margrit Kernbach4, Bettina Baron-Lühr4, Matteo Porotto6, Maria de Sousa3, Eliezer A. Rachmilewitz7, John D. Hood8, M. Domenica Cappellini2, Patricia J. Giardina1, Robert W. Grady1, Johannes Gerdes4, and Stefano Rivella1 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 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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