Retinoic Acid sensitizes acute myeloid leukemia cells to ER stress

Chemotherapy plus retinoic acid (RA) result in cure rates of acute promyelocytic leukemia (APL) exceeding 80%. Although resistant or relapsed patients are effectively treated with arsenic trioxide (ATO) plus RA, elevated costs limit its use. Moreover non-APL AML do not respond to RA indicating the need for novel therapeutic strategies. We show that RA induces ER stress in APL cells slightly activating the unfolded protein response (UPR). This is sufficient to render human leukemic cell lines and primary blasts very sensitive to doses of ER stress inducing drugs, like tunicamycin (Tm), not toxic for the same cells in the absence of RA or for most cell types. Furthermore, low doses of Tm, even in the absence of RA, are sufficient to strongly increase ATO toxicity. Indeed both RA-sensitive and resistant APL cells resulted sensitive to Tm-ATO combined treatment at doses of ATO ineffective in the absence of ER stress. The use of inhibitors targeting specific UPR branches indicates a main role for the PERK pathway. Finally, we extended our observations in a non-APL model, assessing that RA sensitize the non-APL cell line HL60 to ER stress. Thus, our data indicate ER stress as a possible target for novel combination therapeutic strategies in AML.