Ectopic expression of C/EBPα and ID1 is sufficient to restore defective neutrophil development in low-risk myelodysplasia

Autor: Christian R. Geest, Miranda Buitenhuis, Edo Vellenga, Paul J. Coffer
Jazyk: angličtina
Rok vydání: 2009
Předmět:
Zdroj: Haematologica, Vol 94, Iss 8 (2009)
Druh dokumentu: article
ISSN: 0390-6078
1592-8721
DOI: 10.3324/haematol.2008.000471
Popis: 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/EBPα or ID1. Whereas treatment of progenitors with SB203580, PKB or STAT5 did not enhance neutrophil development, ID1- and C/EBPα-transduced cells exhibited increased granulocyte/macrophage colony formation. Furthermore, ectopic expression of C/EBPα resulted in improved neutrophil maturation.Conclusions These data suggest that targeting the ID1 and C/EBPα transcriptional regulators may be of benefit in the design of novel therapies for low-risk myelodysplasia.
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