The AML1 gene, located on chromosome 21, is involved in several distinct chromosomal translocations in human leukemia. In t(8;21) acute myelogenous leukemia (AML), the AML1 gene is juxtaposed to the ETO gene located on chromosome 8, generating an AML1͞ETO fusion protein. Both AML1͞ETO and the AML1 proteins recognize the same consensus DNA-binding motif (TGT͞CGGT), which is found in the promoters of several genes involved in hematopoiesis. We found that two myeloid leukemia cell lines with the t(8;21) translocation, Kasumi and SKNO-1, have elevated levels of BCL-2 protein compared with other myeloid cell lines. In addition, we identified a consensus AML1 binding site in the BCL-2 promoter. Thus far, AML1͞ETO has been shown to dominantly repress its target genes; however, we found that AML1͞ETO activates transcription of the BCL-2 gene in U937 cells. This activation requires the presence of both the runt homology domain (rhd) and the C-terminal portion of AML1͞ ETO. We demonstrated sequence specific binding of both AML1A and AML1͞ETO to the TGTGGT sequence in the BCL-2 promoter and showed that the AML1 binding site is required for responsiveness to AML1͞ETO. Interestingly, AML1A and AML1B do not modulate the activity of the BCL-2 promoter. The elevated levels of BCL-2 in cells that express AML1͞ETO may prolong their life span and contribute to the development of t(8;21) leukemia.Chromosomal translocations found in human leukemia frequently involve genes that code for transcription factors (1). In acute myeloid leukemia (AML) with the t(8;21) chromosomal translocation, which occurs in Ϸ40% cases of AML with the M2 French-American-British subtype, coding sequences of the AML1 gene (on chromosome 21) are juxtaposed to coding sequences of the ETO gene (on chromosome 8) generating an AML1͞ETO fusion protein (2, 3). The AML1 family of transcription factors recognize the binding sequence 5Ј-TGT͞ CGGT-3Ј (2) through an 117-amino acid region that is highly homologous to the Drosophila segmentation gene runt (2, 3), and has been called the runt homology domain (rhd). This domain is necessary for DNA binding, as well as for proteinprotein interactions (3). At least three forms of AML1 protein are produced by alternative splicing (4). The AML1-B isoform (479 amino acids) contains the rhd and a putative C-terminal transcriptional activation domain; the AML1-A isoform (250 amino acids) contains the DNA binding domain, but lacks the potential transcriptional activation domain. AML1-B, but not A ML-1A, can transactivate the human granulocyte͞ macrophage colony-stimulating factor (GM-CSF) promoter (5) and the T cell receptor  enhancer (6), whereas both isoforms can transactivate the human interleukin 3 (IL-3) gene (H.U., S.Z., and S.D.N., unpublished work).The genes encoding AML1 or its dimerization partner CBF, have been shown to be involved in several other translocations in human acute leukemia (7). The AML1 gene is fused to the TEL gene in t(12;21) acute lymphoblastic leukemia (8). In the t(3;21) translocation, seen ...
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