Development of a combination strategy based on ER and oxidative stress in Acute Myeloid Leukemia

We have previously shown that Acute Promyelocytic Leukemia (APL) cell lines and primary blasts are highly sensitive to a combination of Retinoic Acid (RA) and ER and oxidative stress inducers (Tunicamycin, Tm, and Arsenic Trioxide, ATO), at doses not detrimental for healthy hematopoietic progenitors. This treatment caused aggregation of the APL oncoprotein PMLRARα. Thus, mutant or fusion proteins, easily prone to aggregation or mis-folding, could render the cells sensitive to levels of ER and oxidative stress that can be recovered in their absence. We found that Acute Myeloid Leukemia (AML) cells, bearing different fusion proteins and the FLT-3-ITD mutation, are highly sensitive to the combination of sub-lethal amounts of RA, Tm and ATO. We observed prolonged activation of the antioxidant response and of the unfolded protein response (UPR), activated by ER stress. The antioxidant agent N-acetyl-cystenine and a UPR inhibitor determine resistance to the treatments. Importantly, the combination of ER and oxidative stress significantly reduces the colony forming capacity of primary FLT3-ITD positive leukemic blasts, but not of healthy progenitors.