학술논문
Cystine uptake inhibition potentiates front-line therapies in acute myeloid leukemia
Document Type
Article
Author
Pardieu, Bryann; Pasanisi, Justine; Ling, Frank; Dal Bello, Reinaldo; Penneroux, Justine; Su, Angela; Joudinaud, Romane; Chat, Laureen; Wu, Hsin Chieh; Duchmann, Matthieu; Sodaro, Gaetano; Chauvel, Clémentine; Castelli, Florence A.; Vasseur, Loic; Pacchiardi, Kim; Belloucif, Yannis; Laiguillon, Marie-Charlotte; Meduri, Eshwar; Vaganay, Camille; Alexe, Gabriela; Berrou, Jeannig; Benaksas, Chaima; Forget, Antoine; Braun, Thorsten; Gardin, Claude; Raffoux, Emmanuel; Clappier, Emmanuelle; Adès, Lionel; de Thé, Hugues; Fenaille, François; Huntly, Brian J.; Stegmaier, Kimberly; Dombret, Hervé; Fenouille, Nina; Lobry, Camille; Puissant, Alexandre; Itzykson, Raphael
Source
Leukemia; June 2022, Vol. 36 Issue: 6 p1585-1595, 11p
Subject
Language
ISSN
08876924; 14765551
Abstract
By querying metabolic pathways associated with leukemic stemness and survival in multiple AML datasets, we nominated SLC7A11encoding the xCT cystine importer as a putative AML dependency. Genetic and chemical inhibition of SLC7A11impaired the viability and clonogenic capacity of AML cell lines in a cysteine-dependent manner. Sulfasalazine, a broadly available drug with xCT inhibitory activity, had anti-leukemic activity against primary AML samples in ex vivo cultures. Multiple metabolic pathways were impacted upon xCT inhibition, resulting in depletion of glutathione pools in leukemic cells and oxidative stress-dependent cell death, only in part through ferroptosis. Higher expression of cysteine metabolism genes and greater cystine dependency was noted in NPM1-mutated AMLs. Among eight anti-leukemic drugs, the anthracycline daunorubicin was identified as the top synergistic agent in combination with sulfasalazine in vitro. Addition of sulfasalazine at a clinically relevant concentration significantly augmented the anti-leukemic activity of a daunorubicin-cytarabine combination in a panel of 45 primary samples enriched in NPM1-mutated AML. These results were confirmed in vivo in a patient-derived xenograft model. Collectively, our results nominate cystine import as a druggable target in AML and raise the possibility to repurpose sulfasalazine for the treatment of AML, notably in combination with chemotherapy.