Promyelocytic leukemia (APL) is characterized by the chromosomal translocation t(15:17) that results in the expression of the chimeric protein PML-RARα. The fusion of PML, a tumor suppressor that is the major component of the PML-nuclear bodies, with the Retinoic Acid Receptor-α arrests the differentiation program driven by RARα, blocking the leukemic blasts at the promyelocytic stage. Pharmacological doses of Retinoic Acid (RA) are able to remove the block, resume granulocytic differentiation and partially degrade PML-RARα leading to reformation of nuclear bodies. The association of RA with chemotherapy or with arsenic trioxide (ATO), the latter efficiently targeting PML-RARα for degradation, results in high cure rates of acute promyelocytic leukemia (APL). Despite showing a considerably improved safety profile, either RA or ATO are not devoid of toxicity, with the most important and potentially life-threatening one being the so-called retinoic acid differentiation syndrome. We show here that RA-induced differentiation of human APL cell lines and primary blasts dramatically increases their sensitivity to ER stress inducing drugs, like Tunicamycin (Tm), at doses that are not toxic in the absence of RA. Importantly only human progenitors cells derived from APL patients resulted sensitive to the combined treatment with RA and Tm whereas those obtained from healthy donors were not affected. Granulocytic differentiation of APL cells driven by RA triggers a physiological Unfolded Protein Response, a series of pathways emanating from the ER in case of ER stress, which ensues when higher protein folding activity is required as during differentiation. Although mild, the ER stress induced by RA is sufficient to render differentiating APL cells very sensitive to low doses of Tm. We also show that the UPR pathway downstream of PERK plays a major protective role against ER stress in differentiating cells and, by using a specific PERK inhibitor, we potentiated the toxic effect of the combination of RA and Tm. Moreover we found that low amounts of pharmacologically induced ER stress are also able to strongly increase ATO toxicity even in the absence of RA. Indeed the combination of ATO with Tm efficiently induced apoptosis in RA-sensitive and RA resistant APL cell lines, at doses ineffective in the absence of ER stress. Eventually, we demonstrate that insurgency of oxidative stress, tightly linked with the UPR, is at the basis of the toxicity induced by Tm in combination with RA and/or ATO. In conclusion, our findings identify the ER stress-related pathways as potential targets in the search for novel therapeutic strategies in AML.
|Titolo:||Retinoic Acid and Arsenic Trioxide sensitize Acute Promyelocytic Leukemia cells to ER stress|
|Data di pubblicazione:||2017|
|Appartiene alla tipologia:||04d Abstract in atti di convegno|