The t(8;21) and inv(16) are the two most frequent chromosomal abnormalities associated with acute myeloid leukemia. The AML-1 protein, targeted by the (8;21) chromosomal translocation, is a sequence-specific transcriptional regulatory protein whose recognition sequence is required for tissue specific expression of several genes including the T-cell receptor enhancer, lck, IL-3, CSF-1 (in activated T-cells), the myeloperoxidase enhancer, and lactoferrin. Moreover, AML-1 DNA binding activity changes from a rapidly migrating to a more slowly migrating complex during myeloid differentiation, indicating that changes in AML-1 may regulate tissue specific gene expression during in this process. The AML-1 transcription factor complex is composed of two parts, AML-1 contains the site-specific DNA binding activity, whereas CBFbeta interacts with AML-1, but does not bind DNA on its own. Deletion mutagenesis of AML-1 indicated that a domain homologous to the Drosophila pair-rule gene runt, which is retained in the t(8;21) fusion protein, is required for both DNA binding and protein-protein interactions. Recent cloning of the genes involved in the inv(16) has identified a fusion protein containing nearly the entire coding sequence of CBFbeta. Thus, both the t(8;21) and inv(16) act through AmL-1 DNA binding activities. Preliminary data suggest the attractive hypothesis that AML-1 regulated the differentiation of myeloid cells and that expression of the AML/ETO hybrid protein form the t(8;21) disrupts this process leading to malignant transformation. The proposed research will test this hypothesis by defining the transcriptional regulatory activity of AML-1 and AML/ETO in myeloid and lymphoid cell lines and by exploring the regulation of complexes containing AML-1 during myeloid differentiation. The ability of AML/ETO to block differentiation or provide a growth advantage will be assessed by ectopic expression in cell lines as well as primary hematopoietic progenitor cells. The targeting of the AmL-1 transcription factor complex by two independent chromosomal translocations, leading to 30-40% of AML cases strongly argues that AML-1 is a key regulator of cellular differentiation and/or proliferation. Understanding the role of AmL-1 and MAL/ETO in the control circuits governing normal hematopoiesis should yield important information about the genesis of human acute leukemia and suggest possible avenues for therapeutic intervention.
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