Absence of the Transcription Factor Ccaat Enhancer Binding Protein Alpha Results in Loss of Myeloid Identity in Bcr/Abl-induced Malignancy.
From: Harvard Institutes of Medicine, Room 954, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
Proceedings of the National Academy of Sciences of the United States of America
- Publish Date: Apr 2006
- ISSN: 0027-8424
- Volume: 103
- Issue: 16
- Pages: 6338-43
- Medium: Print
- Language: English
- Citation (JAMA): Wagner Katharina, Zhang Pu, Rosenbauer Frank, et al. Absence of the Transcription Factor Ccaat Enhancer Binding Protein Alpha Results in Loss of Myeloid Identity in Bcr/Abl-induced Malignancy.. Proc. Natl. Acad. Sci. U.S.A. Apr 2006;103:6338-43
Abstract
The lineage-determining transcription factor CCAAT enhancer binding protein alpha (C/EBPalpha) is required for myeloid differentiation. Decreased function or expression of C/EBPalpha is often found in human acute myeloid leukemia. However, the precise impact of C/EBPalpha deficiency on the maturation arrest in leukemogenesis is not well understood. To address this question, we used a murine transplantation model of a bcr/abl-induced myeloproliferative disease. The expression of bcr/abl in C/EBPalphapos fetal liver cells led to a chronic myeloid leukemia-like disease. Surprisingly, bcr/abl-expressing C/EBPalpha-/- fetal liver cells failed to induce a myeloid disease in transplanted mice, but caused a fatal, transplantable erythroleukemia instead. Accordingly, increased expression of the transcription factors SCL and GATA-1 in hematopoietic precursor cells of C/EBPalpha-/-R01-EY-11298 ) fetal livers was found. The mechanism for the lineage shift from myeloid to erythroid leukemia was studied in a bcr/abl-positive cell line. Consistent with findings of the transplant model, expression of C/EBPalpha and GATA-1 was inversely correlated. Id1, an inhibitor of erythroid differentiation, was identified as a critical direct target of C/EBPalpha. Down-regulation of Id1 by RNA interference impaired C/EBPalpha-induced granulocytic differentiation. Taken together, our study provides evidence that myeloid lineage identity of malignant hematopoietic progenitor cells requires the residual expression of C/EBPalpha.
Mesh Headings (Keywords): Animals, Basic Helix-Loop-Helix Transcription Factors, CCAAT-Enhancer-Binding Protein-alpha, Cell Differentiation, Fusion Proteins, bcr-abl, GATA1 Transcription Factor, Hematopoietic Stem Cells, Inhibitor of Differentiation Protein 1, Leukemia, Erythroblastic, Acute, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Mice, Myeloid Cells, Neoplasm Transplantation, Proto-Oncogene Proteins, RNA Interference, Transcription Factors, Transfection, Up-Regulation, Xenograft Model Antitumor Assays
Check for Full Text / PubMed Unique Identifier (PMID): 16606850
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