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

Abstract

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. ©2009 Ferrata Storti Foundation.