Retinoic acid synergizes with the unfolded protein response and oxidative stress to induce AML cell death

Acute Myeloid Leukemia (AML) is often characterized by the expression of fusion or mutant proteins that cause impaired differentiation and enhanced proliferation and survival. The presence of mutant proteins prone to misfolding can render the cells sensitive to endoplasmic reticulum (ER) and oxidative stress that could otherwise be overcome. We aim at exploiting cellular stresses to hit AML cells. Methods We treated AML cell lines and primary blasts expressing mutant proteins with the differentiating agent retinoic acid (RA), the ER stress-inducing drug Tunicamycin (Tm) and arsenic trioxide (ATO), able to generate oxidative stress, at doses that result no or only slightly toxic when each drug was used alone. Results We show that the triple combination of RA, Tm and ATO, leads to death of AML cell lines and primary leukemic cells bearing fusion proteins involving the gene MLL and the internal tandem duplication (ITD) in the FLT3 tyrosine kinase receptor. Importantly, primary healthy hematopoietic progenitor cells are not affected by this treatment. We demonstrate in cell lines, that combination of these drugs not only generates ER and oxidative stress, but also impairs maturation and causes accumulation of FLT3 protein in the ER. Our data provide a proof of concept that low amounts of drugs that generate ER and oxidative stress combined with RA could be an effective targeted therapy to hit AML cells characterized by MLL fusion proteins and FLT3-ITD mutation.