Standard treatment for AML is a combination of an anthracycline (daunorubicin;DNR) and a cytarabine. However, anthracyclines have toxic effect on normal cells and are potentially mutagenic. A rare example of successful differentiation therapy is provided in promyelocytic leukemia (APL), which undergo remission in response to retinoic acid (ATRA), and most often are cured when ATRA is combined with a low dose of anthracycline. Data provided by Dr.Lanotte suggest that cAMP elevating agents could enhance the action of ATRA and that ATRA and cAMP could decrease even further the dose of anthracycline required to cure APL. We demonstrate that the cAMP elevating agent PGE2, elevated in the bone marrow during inflammation, protect NB4 cells against DNR- induced apoptosis. The main protective effect observed by cAMP was mediated via PKA rather than Epac and the addition of the analogs could be delayed until 2.5 hours into DNR treatment and still have significant protective effect. The RI and RII isoforms of PKA are differently distributed throughout cells and tissues and isoform specific analogs imply that the cAMP protection was mediated mainly by PKA type I. In support of this, the ability of cAMP to protect against DNR was intact in NB4 cells with knocked- down RII. We conclude that cAMP and ATRA stimulation should be employed separately from anthracycline The finding that PKA type I could be activated selectively enables the use of PKA typeI-directed cAMP analogs which will decrease potential side- effects from organs like brain, adipose tissue and heart.