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


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/EBPalpha or ID1. Whereas treatment of progenitors with SB203580, PKB or STAT5 did not enhance neutrophil development, ID1- and C/EBPalpha-transduced cells exhibited increased granulocyte/macrophage colony formation. Furthermore, ectopic expression of C/EBPalpha resulted in improved neutrophil maturation.


CONCLUSIONS
These data suggest that targeting the ID1 and C/EBPalpha transcriptional regulators may be of benefit in the design of novel therapies for low-risk myelodysplasia.
Geest
Christian R
CR
Department of Immunology, University Medical Center, Utrecht, The Netherlands.
Buitenhuis
Miranda
M
Vellenga
Edo
E
Coffer
Paul J
PJ
D000328:Adult; D000368:Aged; D018952:Antigens, CD34 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D015870:Gene Expression; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D006412:Hematopoietic Stem Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007150:Immunohistochemistry; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000097:blood*; D009504:Neutrophils / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D050799:STAT5 Transcription Factor / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D018952:Antigens, CD34; D022763:CCAAT-Enhancer-Binding Protein-alpha; C497453:ID1 protein, human; D007093:Imidazoles; D051798:Inhibitor of Differentiation Protein 1; D011725:Pyridines; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; D025521:Tumor Suppressor Proteins; D016179:Granulocyte Colony-Stimulating Factor; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580