Decreased differentiation of erythroid cells exacerbates ineffective erythropoiesis in β-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-Lühr, Matteo Porotto, Maria De Sousa, Eliezer A. Rachmilewitz, John D. Hood, M. Domenica Cappellini, Patricia J. Giardina, Robert W. Grady, Johannes Gerdes, Stefano Rivella

Research output: Contribution to journalArticle

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-67and the antiapoptotic protein BcIX L. 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.

Original languageEnglish
Pages (from-to)875-885
Number of pages11
JournalBlood
Volume112
Issue number3
DOIs
Publication statusPublished - Aug 1 2008

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Erythroid Cells
Thalassemia
Erythropoiesis
Cells
Apoptosis
Cell Differentiation
Cyclin A
Genes
cdc Genes
Erythroblasts
S Phase
Anemia
Proteins
Spleen
TG101209

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Libani, I. V., Guy, E. C., Melchiori, L., Schiro, R., Ramos, P., Breda, L., ... Rivella, S. (2008). Decreased differentiation of erythroid cells exacerbates ineffective erythropoiesis in β-thalassemia. Blood, 112(3), 875-885. https://doi.org/10.1182/blood-2007-12-126938

Decreased differentiation of erythroid cells exacerbates ineffective erythropoiesis in β-thalassemia. / 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.

In: Blood, Vol. 112, No. 3, 01.08.2008, p. 875-885.

Research output: Contribution to journalArticle

Libani, IV, Guy, EC, Melchiori, L, Schiro, R, Ramos, P, Breda, L, Scholzen, T, Chadburn, A, Liu, Y, Kernbach, M, Baron-Lühr, B, Porotto, M, De Sousa, M, Rachmilewitz, EA, Hood, JD, Cappellini, MD, Giardina, PJ, Grady, RW, Gerdes, J & Rivella, S 2008, 'Decreased differentiation of erythroid cells exacerbates ineffective erythropoiesis in β-thalassemia', Blood, vol. 112, no. 3, pp. 875-885. https://doi.org/10.1182/blood-2007-12-126938
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. / Decreased differentiation of erythroid cells exacerbates ineffective erythropoiesis in β-thalassemia. In: Blood. 2008 ; Vol. 112, No. 3. pp. 875-885.
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AU - Ramos, Pedro

AU - Breda, Laura

AU - Scholzen, Thomas

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