Retinoic acid synergizes with the unfolded protein response and oxidative stress to induce cell death in FLT3-ITD+ AML.

Silvia Masciarelli, Luca Tamagnone, Ernestina Capuano, Tiziana Ottone, Mariadomenica Divona, Serena Lavorgna, Francesca Liccardo, Martyna Śniegocka, Serena Travaglini, Nelida I. Noguera, Alessandra Picardi, Vincenzo Petrozza, Alessandro Fatica, Francesco Lo Coco, Francesco Fazi

Risultato della ricerca: Contributo in rivistaArticolo in rivista

8 Citazioni (Scopus)

Abstract

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) stress and oxidative stress that could otherwise be overcome. Here, we show that the triple combination of the differentiating agent retinoic acid (RA), the ER stress-inducing drug tunicamycin (Tm), and arsenic trioxide (ATO), able to generate oxidative stress, leads to the death of AML cell lines expressing fusion proteins involving the gene MLL and the internal tandem duplication (ITD) in the FLT3 tyrosine kinase receptor. Importantly, the combination of RA, Tm, and ATO decreased the colony-forming capacity of primary leukemic blasts bearing the FLT-ITD mutation without affecting healthy hematopoietic progenitor cells. We demonstrate in cell lines that combination of these drugs generates ER and oxidative stresses and 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 stresses combined with RA could be an effective targeted therapy to hit AML cells characterized by MLL fusion proteins and FLT3-ITD mutation.
Lingua originaleEnglish
pagine (da-a)4155-4160
Numero di pagine6
RivistaBLOOD ADVANCES
Volume3
DOI
Stato di pubblicazionePubblicato - 2019

Keywords

  • Acute myeloid leukemia (AML)
  • endoplasmic reticulum (ER)

Fingerprint

Entra nei temi di ricerca di 'Retinoic acid synergizes with the unfolded protein response and oxidative stress to induce cell death in FLT3-ITD+ AML.'. Insieme formano una fingerprint unica.

Cita questo