Cooperative effects of a DNMT inhibitor and all-trans retinoic acid in an AML cell line model lacking PML-RARA

Introduction: All-trans retinoic acid (ATRA, RA) has powerful activity in acute promyelocytic leukemia (APL); its efficacy in non-APL acute myeloid leukemia (AML) is still unclear, but may be enhanced by epigenetic drugs such as azanucleoside DNMT inhibitors (Blagitko-Dorfs et al. PLoS ONE 2013). In a randomized phase II study (DECIDER trial, NCT00867672) the addition of RA to decitabine (DAC) in newly diagnosed non-fit older AML patients resulted in a clinically meaningful extension of survival. We hypothesize that the add-on of RA to DAC results in cooperative transcriptome changes (possibly associated with demethylation) which may, at least in part, explain these clinical results.