chromatin structure-driven epigenetic  therapy in myeloid neoplasms

“Epigenetics” refers to modifications of DNA, DNA-associated proteins, and/or RNA interference that alter chromatin structure and gene expression, while the DNA sequence remains unchanged. Drugs that target various components of the epigenetic machinery have proven to be effective treatments for myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).  However, only some MDS/AML patients respond to such drugs, and the mechanisms underlying the selectivity and efficacy of epigenetic drugs in these patients are unknown. Therefore, there is an urgent clinical need for new methods to direct effective epigenetic therapy. This proposal seeks to develop a novel approach to address this need by identification of drug-sensitive chromatin structure in MDS and AML. This study is based on the investigator’s recent discovery of different drug-sensitive chromatin structure at a key blood development gene, PU.1/SPI1, in two subtypes of leukemia. The preliminary data show that despite having different underlying genetic abnormalities, AML cell-lines with the same drug-sensitive chromatin structure at the PU.1/SPI1 gene locus respond to the same types of epigenetic drugs, whereas AML cell-lines with different chromatin structure require different therapy. Based on these data, the investigators hypothesize that the functional chromatin status of the key lineage/differentiation-controlling genes determines the differential response to epigenetic-modifying drugs in various myeloid neoplasms. The proposed study has two specific aims: 1) to identify the key factors that physically and/or functionally interact with PU.1/SPI1 to form the drug-sensitive chromatin structure in erythroid and monocytic leukemia cells, and 2) to establish a genome-wide map of drug-sensitive chromatin structure in MDS and AML.