Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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Wagner, K. et al.

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

The lineage-determining transcription factor CCAAT enhancer binding protein alpha (C/EBPalpha) is required for myeloid differentiation. Decreased function or expression of C/EBPalpha is often found in human acute myeloid leukemia. However, the precise impact of C/EBPalpha 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/EBPalpha(pos) fetal liver cells led to a chronic myeloid leukemia-like disease. Surprisingly, bcr/abl-expressing C/EBPalpha(-/-) 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/EBPalpha(-/-) 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/EBPalpha and GATA-1 was inversely correlated. Id1, an inhibitor of erythroid differentiation, was identified as a critical direct target of C/EBPalpha. Down-regulation of Id1 by RNA interference impaired C/EBPalpha-induced granulocytic differentiation. Taken together, our study provides evidence that myeloid lineage identity of malignant hematopoietic progenitor cells requires the residual expression of C/EBPalpha.[1]

References

Absence of the transcription factor CCAAT enhancer binding protein {alpha} results in loss of myeloid identity in bcr/abl-induced malignancy. Wagner, K., Zhang, P., Rosenbauer, F., Drescher, B., Kobayashi, S., Radomska, H.S., Kutok, J.L., Gilliland, D.G., Krauter, J., Tenen, D.G. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]

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