The work in my laboratory focuses on determining the normal function of the AML1/RUNX1and ETO family of transcription factors in the regulation of stem cells and gene expression, and how disruption of these genes by chromosomal translocations causes myeloid leukemia. We defined AML1 as a transcription factor that binds the "enhancer core" motif, which regulates the expression of a large number of tissue specific genes. We found that AML1 both activates and represses transcription, and that the translocation fusion proteins inhibit expression of AML1-dependent target genes. We have determined that the t(8;21) fusion protein, AML1/ETO, interacts with the mSin3 and nuclear hormone co-repressors that recruit histone deacetylases to repress transcription. Thus, we have identified a common mechanism for transcriptional repression for these three translocations. Given that these fusion proteins recruit epigenetic modifying enzymes, we are targeting these factors to determine if we can cure this leukemia. We use CRISPR-mediated genetics to modify AML1-ETO for rapid degradation to define its direct target genes. We use cutting-edge genomics methods such as PROseq coupled with small molecule drugs to inhibit chromatin-modifying enzymes to define the mechanism of tumorigenesis and how to attack this cancer.