AML is a very heterogeneous disease caused by different genetic aberrations that in all cases cause impaired differentiation and enhanced proliferation and survival of hematopoietic progenitor cells. Among AMLs only APL, expressing PML-RARα fusion protein, respond well to retinoic acid (RA) and/or arsenic trioxide (ATO) based treatments. RA-induced differentiation of APL leukemic blasts is characterized by the production of secretory granules and by an increased activity of the ER with a slight activation of the Unfolded Protein Response (UPR). We have previously shown that APL cell lines and primary blasts treated with RA or ATO, an oxidative agent, become highly sensitive to amounts of ER stress not detrimental for the same cells in the absence of RA. Importantly we observed that ER stress caused increased amounts of disulphide-bound high molecular weight aggregates of PMLRARα and PML, exacerbating the alteration of cellular proteostasis. We reasoned that this observation could provide the bases to apply the same principles to other types of AML characterized by fusion or mutant proteins. Here we show that the ML-2 cell line, bearing the MLL-AF6 fusion protein, is sensitive to the combination of the ER-stress inducing drug Tunicamycin (Tm) and ATO independently of RA, whereas the MV-4-11 cell line, expressing the fusion protein MLL-AF4 and the mutant FLT-3-ITD resulted already sensitive to the combination of RA and Tm whose toxicity was augmented by ATO. Moreover, we show that the mutant protein FLT-3-ITD, matured along the secretory pathway, markedly accumulates in the Golgi apparatus upon administration of low doses of Tm in combination with RA and to a lesser extent upon treatment with ATO. In conclusion, our insights could contribute to the identification of new molecular targets like the ER stress response that would allow the design of new AML subtype related therapeutic strategies.
|Titolo:||Development of a combination strategy based on ER and oxidative stress in acute myeloid leukemia|
|Data di pubblicazione:||2017|
|Appartiene alla tipologia:||04d Abstract in atti di convegno|