Helmholtz Gemeinschaft


Absence of the transcription factor CCAAT enhancer binding protein alpha results in loss of myeloid identity in bcr/abl-induced malignancy

Item Type:Article
Title:Absence of the transcription factor CCAAT enhancer binding protein alpha results in loss of myeloid identity in bcr/abl-induced malignancy
Creators Name:Wagner, K., Zhang, P., Rosenbauer, F., Drescher, B., Kobayashi, S., Radomska, H.S., Kutok, J.L., Gilliland, D.G., Krauter, J. and Tenen, D.G.
Abstract:The lineage-determining transcription factor CCAAT enhancer binding protein {alpha}(C/EBP{alpha}) is required for myeloid differentiation. Decreased function or expression of C/EBP{alpha} is often found in human acute myeloid leukemia. However, the precise impact of C/EBP{alpha} 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/EBP{alpha} pos fetal liver cells led to a chronic myeloid leukemia-like disease. Surprisingly, bcr/abl-expressing C/EBP{alpha} -/- 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/EBP{alpha} -/- 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/EBP{alpha} and GATA-1 was inversely correlated. Id1, an inhibitor of erythroid differentiation, was identified as a critical direct target of C/EBP{alpha}. Down-regulation of Id1 by RNA interference impaired C/EBP{alpha}-induced granulocytic differentiation. Taken together, our study provides evidence that myeloid lineage identity of malignant hematopoietic progenitor cells requires the residual expression of C/EBP{alpha}.
Keywords:Acute Erythroblastic Leukemia, Basic Helix-Loop-Helix Transcription Factors, BCR-ABL Chronic Myelogenous positive Leukemia, BCR-ABL Fusion Proteins, CCAAT-Enhancer-Binding Protein-alpha, Cell Differentiation, GATA1 Transcription Factor, Hematopoietic Stem Cells, Inhibitor of Differentiation Protein 1, Myeloid Cells, Neoplasm Transplantation, Proto-Oncogene Proteins, RNA Interference, Transcription Factors, Transfection, Up-Regulation, Xenograft Model Antitumor Assays, Animals, Mice
Source:Proceedings of the National Academy of Sciences of the United States of America
Publisher:National Academy of Sciences
Page Range:6338-6343
Date:18 April 2006
Official Publication:https://doi.org/10.1073/pnas.0508143103
PubMed:View item in PubMed

Repository Staff Only: item control page

Open Access
MDC Library