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Cystine uptake inhibition potentiates front-line therapies in acute myeloid leukemia.

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Pardieu, Bryann 
Pasanisi, Justine 
Ling, Frank 
Dal Bello, Reinaldo 
Penneroux, Justine 

Abstract

By querying metabolic pathways associated with leukemic stemness and survival in multiple AML datasets, we nominated SLC7A11 encoding the xCT cystine importer as a putative AML dependency. Genetic and chemical inhibition of SLC7A11 impaired 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.

Description

Keywords

Cell Line, Tumor, Cysteine, Cystine, Daunorubicin, Humans, Leukemia, Myeloid, Acute, Nuclear Proteins, Sulfasalazine

Journal Title

Leukemia

Conference Name

Journal ISSN

0887-6924
1476-5551

Volume Title

Publisher

Springer Science and Business Media LLC
Sponsorship
Cancer Research UK (25508)