The overall goal of our research is the development of better translational approaches to cancer treatment through elucidation of the molecular mechanisms, in particular epigenetic processes, underlying transcriptional deregulation and pathogenesis of acute myeloid leukemia (AML). Although all-trans-retinoic acid (ATRA) has held a great promise for anti-AML therapy, with the exception of acute promyelocytic leukemia (APL) ATRA treatment has not been successful in other types of AML. During hematopoiesis, ATRA, a natural derivative of vitamin A, has been shown to induce both myelomonocytic progenitor/stem cell differentiation and self-renewal. Although these opposing effects are likely to be partly due to developmental differences, it has been shown that pro- and anti-differentiation effects of ATRA are mediated by distinct retinoic acid receptor isotypes (RARα and RARγ, respectively). Given these findings, we have previously hypothesized that one of the underlying reasons for the poor response of non-APL AML to ATRA (pan-RAR agonist) is aberrant expression and/or activities of RAR isotypes favoring RARγ and cell growth versus differentiation. Consistently, we have reported that expression of RARα isoforms, particularly ATRA-inducible RARα2, are down-regulated in AML (Blood. 2008; 111:2374). Epigenetic analyses of AML patient samples has revealed that relative to normal CD33+ cells, loss of expression of the pro-differentiation RARα2 nuclear receptor in AML is not due to DNA methylation, as previously thought, but linked with histone H3 methylation changes that negatively impact transcription from the RARA2 promoter, and possibly other ATRA responsive genes whose expression is required for AML cell differentiation. Reversal of these negatively-acting epigenetic changes by either pharmocological or genetic means restores the ATRA-responsiveness of the myelomonocytic differentiation-associated gene expression program of AML cell lines as well as primary patient derived AML cells in vitro and in vivo. Collectively, our data demonstrate the existence of therapeutically relevant crosstalks between the ATRA-induced differentiation pathway and histone methylation and pave the way for effective use of ATRA in combination therapy to treat non-APL AMLs.