期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2006
卷号：103
期号：16
页码：6338-6343
DOI：10.1073/pnas.0508143103
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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}.
