AML1-MTG8 leukemic protein induces the expression of granulocyte colony-stimulating factor (G-CSF) receptor through the up-regulation of CCAAT/enhancer binding protein epsilon

The t(8;21) translocation is one of the most frequent chromosomal abnormali ties associated with acute myeloid leukemia (AML). In this translocation, t he AML1 (CBFA2/PEBP2aB) gene is disrupted and fused to the MTG8 (ETO) gene. The ectopic expression of the resulting AML1-MTG8 fusion gene product in L -G and 32Dc13 murine myeloid precursor cells stimulates cell proliferation without inducing morphologic terminal differentiation into mature granulocy tes in response to granulocyte-colony stimulating factor (G-CSF). This stud y found that the ectopic expression of AML1-MTG8 elevates the expression of the G-CSF receptor (G-CSFR). Analysis of the promoter region of the G-CSFR gene revealed that up regulation of G-CSFR expression by AML1-MTG8 does no t depend on the AML1-binding sequence, but on the C/EBP (CCAAT/enhancer bin ding protein) binding site. The results suggest that the overproduction of G-CSFR is at least partly mediated by C/EBP epsilon, whose expression is ac tivated by AML1-MTG8. The ectopic expression of G-CSFR in L-G cells induced cell proliferation in response to G-CSF, but did not inhibit cell differen tiation into mature neutrophils. Overexpression of C/EBP epsilon in L-G cel ls also stimulated G-CSF-dependent cell proliferation. High expression leve ls of G-CSFR were also found in the leukemic cells of AML patients with t(8 ;21). Therefore, G-CSF-dependent cell proliferation of myeloid precursor ce lls may be implicated in leukemogenesis. (Blood. 2000;96: 288-296) (C) 2000 by The American Society of Hematology.