University of North Carolina Chapel Hill Chapel Hill United States
Direct sequencing of hematopoietic cancers identified gain-of-function mutations of EZH2, the gene encoding the enzymatic subunit of Polycomb Repressive Complex-2 PRC2, among 10 germ-center B-cell lymphomas. EZH2 silences gene expression through catalysis of methylation of histone H3 lysine 27. However, the currently available EZH2-specific inhibitors are ineffective for treating EZH2-wildtype lymphomas. Novel therapeutics needs to be developed. We found overexpression of PHF19, a PRC2-associated cofactor, is common among B-cell derived malignancies. During this funding period, we have made significant progress in testing our central hypothesis is that, overexpression of PHF19 confers oncogenicity to lymphoma by either enhancing enzymatic activities or chromatin association of PRC2 complexes in addition, we have evaluated the pan PRC2 inhibitor as a novel means for blockade of unwanted PRC2 hyperactivities among blood cancers including B-cell malignancies.