My laboratory has been studying the transcriptional regulation of normal and malignant hematopoiesis. We have studied the AML1-ETO leukemia-promoting oncogene, defining its target genes, its ability to promote stem cell self-renewal, and more recently, have been trying to target its activity therapeutically. Over the past several years, we reported that acetylation of this oncogene is absolutely required for leukemogenesis, and that targeting the p300 acetyltransferase can prolong the survival of mice with AML1-ETO driven leukemia (Science 2011). We also reported (Nature 2013) that upon oligomerization, several critical protein-protein interactions involving AML1-ETO can be targeted therapeutically.

A main focus of our research is to overcome the most significant clinical challenge in leukemia: the persistence of chemotherapy resistant cells that leads to disease relapse in a majority of patients. We are investigating the functional cooperativity between genetic lesions and epigenetic factors, both of which are hallmarks of leukemia. Epigenetic regulators are frequently dysfunctional or aberrantly expressed in cancer, thus, targeting these enzymes is a promising therapeutic approach for cancer. We are currently focused on a family of enzymes, the protein arginine methyltransferases (PRMTs), which add methyl marks on arginine residues in histone and non-histone proteins. CARM1 and PRMT5, two major PRMTs in mammalian cells, are often over-expressed in AML, in lymphoma and in solid tumor cells. We have generated and are using various genetically modified mice to identify the role these proteins play in leukemogenesis.

We have also been studying Myelodysplastic syndromes (MDS), a group of heterogeneous diseases that affect the bone marrow's ability to produce mature blood cells. The disease can be mild or life threatening and the risk of progression to acute myeloid leukemia (AML) can be high. Using faithful models of the disease, we are exploring the relationship between MDS development and stem cell self-renewal. Deciphering which mutations or events trigger MDS and disease progression is critical to develop new personalized therapies. My laboratory is especially interested in understanding the role of histone acetyltransferases, such as p300, in the pathogenesis of MDS.