Histone deacetylase-targeted treatment restores retinoic acid signaling and differentiation in acute myeloid leukemia

Histone deacetylase (HDAC)-dependent transcriptional repression of the reti noic acid (RA)-signaling pathway underlies the differentiation block of acu te promyelocytic leukemia. RA treatment relieves transcriptional repression and triggers differentiation of acute promyelocytic leukemia blasts, leadi ng to disease remission. We report that transcriptional repression of RA si gnaling is a common mechanism in acute myeloid leukemias (AMLs). HDAC inhib itors restored RA-dependent transcriptional activation and triggered termin al differentiation of primary blasts from 23 AML patients. Accordingly, we show that AML1/ETO, the commonest AML-associated fusion protein, is an HDAC -dependent repressor of RA signaling. These findings relate alteration of t he RA pathway to myeloid leukemogenesis and underscore the potential of tra nscriptional/ differentiation therapy in AML.