Inhibitors of histone deacetylase relieve ETO-mediated repression and induce differentiation of AML1-ETO leukemia cells

The (8;21) translocation, found in 12% of acute myeloid leukemia (AML), cre ates the chimeric fusion product, AML1-ETO. Previously, we demonstrated tha t the ETO moiety recruits a transcription repression complex that includes the histone deacetylase (HDAC1) enzyme, Here, we used inhibitors of HDAC1 t o study the pathophysiology of AML1-ETO. Both the potent inhibitor, trichos tatin (TSA), and the Hell-known but less specific inhibitor, phenylbutyrate (PB), could partially reverse ETO-mediated transcriptional repression. PB was also able to induce partial differentiation of the AML1-ETO cell line, Kasumi-1. With the intention of developing a clinically useful protocol, we combined PB with a number of other agents that induced differentiation and apoptosis of Kasumi-1 cells, In summary, transcriptional repression mediat ed by AML1-ETO appears to play a mechanistic role in the t(8;21) AML, and r elief of repression using agents such as PB (alone or in combination) may p rove to be therapeutically useful.