Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 103, Issue 16, Pages 6338-6343Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0508143103
Keywords
differentiation; leukemia; lineage commitment
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Funding
- NCI NIH HHS [P30 CA006516, R01 CA088046, P30CA6516, CA88046, CA66996, P01 CA066996] Funding Source: Medline
- NIDDK NIH HHS [K01 DK062064, DK62064] Funding Source: Medline
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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.
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