Haematologica, Vol 94, Issue 8, 1075-1084 doi:10.3324/haematol.2008.000471
Copyright © 2009 by Ferrata Storti Foundation
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Myelodysplastic Syndromes

Ectopic expression of C/EBP{alpha} and ID1 is sufficient to restore defective neutrophil development in low-risk myelodysplasia

Christian R. Geest1, Miranda Buitenhuis1, Edo Vellenga2, Paul J. Coffer1,3

1 Molecular Immunology Laboratory, Department of Immunology, University Medical Center, Utrecht
2 Department of Hematology, University Medical Center, Groningen
3 Department of Pediatric Immunology, University Medical Center Utrecht, Utrecht, The Netherlands

Correspondence: Paul J. Coffer, Dept. Of Immunology and Pediatric Immunology, University Medical Center Utrecht, Lundlaan 6, 3584 CX Utrecht, The Netherlands E-mail:p.j.coffer{at}umcutrecht.nl

Background: In patients with myelodysplasia, a general defect in the multipotent stem-cell compartment results in disturbed proliferation and differentiation of the erythroid, megakaryocytic and myeloid lineages. Although a number of genetic defects in myelodysplastic progenitor cells have been described, the intracellular signaling pathways underlying aberrant regulation of myelopoiesis remain relatively undefined.

Design and Methods: Here, an ex vivo differentiation system was used to selectively screen for molecules improving defective hematopoiesis in myelodysplastic CD34+ progenitor cells.

Results: Bone marrow-derived CD34+ cells isolated from patients with low-risk myelodysplastic syndrome showed impaired capacity to proliferate and differentiate as well as increased levels of apoptosis. In an attempt to improve the expansion and differentiation of the myelodysplastic CD34+ progenitors, cells were treated with the p38MAPK pharmacological inhibitor SB203580, or retrovirally transduced to ectopically express active protein kinase B (PKB/c-akt), or the transcriptional regulators STAT5, C/EBP{alpha} or ID1. Whereas treatment of progenitors with SB203580, PKB or STAT5 did not enhance neutrophil development, ID1- and C/EBP{alpha}-transduced cells exhibited increased granulocyte/macrophage colony formation. Furthermore, ectopic expression of C/EBP{alpha} resulted in improved neutrophil maturation.

Conclusions: These data suggest that targeting the ID1 and C/EBP{alpha} transcriptional regulators may be of benefit in the design of novel therapies for low-risk myelodysplasia.

Key words: myelodysplastic syndrome, myeloid, ID1, C/EBP{alpha}, hematopoiesis.