The growth suppressor PML represses transcription by functionally and physically interacting with histone deacetylases

The growth suppressor promyelocytic leukemia protein (PML) is disrupted by the chromosomal translocation t(15;17) in acute promyelocytic leukemia (APL ). PML plays a key role in multiple pathways of apoptosis and regulates cel l cycle progression. The present study demonstrates that PML represses tran scription by functionally and physically interacting with histone deacetyla se (HDAC). Transcriptional repression mediated by PML can be inhibited by t richostatin A, a specific inhibitor of HDAC. PML coimmunoprecipitates a sig nificant level of HDAC activity in several cell lines. PML is associated wi th HDAC in vivo and directly interacts with HDAC in vitro. The fusion prote in PML-RAR alpha encoded by the t(15;17) breakpoint interacts with HDAC poo rly. PML interacts with all three isoforms of HDAC through specific domains , and its expression deacetylates histone H3 in vivo. Together, the results of our study show that PML modulates histone deacetylation and that loss o f this function in APL alters chromatin remodeling and gene expression. Thi s event may contribute to the development of leukemia.