THE CHIMERIC GENES AML1 MDS1 AND AML1/EAP INHIBIT AML1B ACTIVATION ATTHE CSF1R PROMOTER, BUT ONLY AML1/MDS1 HAS TUMOR-PROMOTER PROPERTIES/

The (3;21)(q26;q22) translocation associated with treatment-related my elodysplastic syndrome, treatment-related acute myeloid leukemia, and blast crisis of chronic myeloid leukemia results in the expression of the chimeric genes AML1/EAP, AML1/MDS1, and AML1/EV11. AML1 (CBFA2), w hich codes for the alpha subunit of the heterodimeric transcription fa ctor CBF, is also involved in the t(8;21), and the gene coding for the beta subunit (CBFB) is involved in the inv(16), These are two of the most common recurring chromosomal rearrangements in acute myeloid leuk emia, CBF corresponds to the murine Pebp2 factor, and CBF binding site s are found in a number of eukaryotic and viral enhancers and promoter s, We studied the effects of AML1/EAP and AML1/MDS1 at the AML1 bindin g site of the CSF1R (macrophage-colony-stimulating factor receptor gen e) promoter by using reporter gene assays, and we analyzed the consequ ences of the expression of both chimeric proteins in an embryonic rat fibroblast cell line (Rat1A) in culture and after injection into athym ic nude mice, Unlike AML1, which is an activator of the CSF1R promoter , the chimeric proteins did not transactivate the CSF1R promoter site but acted as inhibitors of AML1 (CBFA2), AML1/EAP and AML1/MDS1 expres sed in adherent Rat1A cells decreased contact inhibition of growth, an d expression of AML1/MDS1 was associated with acquisition of the abili ty to grow in suspension culture. Expression of AML1/MDS1 increased th e tumorigenicity of Rat1A cells injected into athymic nude mice, where as AML1/EAP expression prevented tumor growth, These results suggest t hat expression of AML1/EAP and AML1/MDS1 can interfere with normal AML 1 function, and that AML1/MDS1 has tumor-promoting properties in an em bryonic rat fibroblast cell line.