1. Absence of the transcription factor CCAAT enhancer binding protein [alpha] results in loss of myeloid identity in bcr/abl-induced malignancy
- Author
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Wagner, Katharina, Zhang, Pu, Rosenbauer, Frank, Drescher, Bettina, Kobayashi, Susumu, Radomska, Hanna S., Kutok, Jeffery L., Gilliland, D. Gary, Krauter, Jurgen, and Tenen, Daniel G.
- Subjects
Leukemia -- Chemical properties ,Leukemia -- Genetic aspects ,Genetic transcription -- Chemical properties ,Science and technology - 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].sup.Pos] fetal liver cells led to a chronic myeloid leukemia-like disease. Surprisingly, bcr/abl-expressing C/EBP[[alpha].sup.-/-] 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].sup.-/-] 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]. differentiation | leukemia | lineage commitment
- Published
- 2006