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. and Zhang, P. and Rosenbauer, F. and Drescher, B. and Kobayashi, S. and Radomska, H.S. and Kutok, J.L. and Gilliland, D.G. and 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
ISSN:	0027-8424
Publisher:	National Academy of Sciences
Volume:	103
Number:	16
Page Range:	6338-6343
Date:	18 April 2006
Official Publication:	https://doi.org/10.1073/pnas.0508143103
PubMed:	View item in PubMed

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