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Article Dans Une Revue Leukemia Année : 2022

Cystine Uptake Inhibition Potentiates Front-Line Therapies In Acute Myeloid Leukemia

Eshwar Meduri
  • Fonction : Auteur
Brian J Huntly
  • Fonction : Auteur
Kimberly Stegmaier
  • Fonction : Auteur
Hervé Dombret
  • Fonction : Auteur

Résumé

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.
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Dates et versions

hal-04053984 , version 1 (31-03-2023)

Identifiants

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Bryann Pardieu, Justine Pasanisi, Frank Ling, Reinaldo Dal Bello, Justine Penneroux, et al.. Cystine Uptake Inhibition Potentiates Front-Line Therapies In Acute Myeloid Leukemia. Leukemia, 2022, 36 (6), pp.1585-1595. ⟨10.1038/s41375-022-01573-6⟩. ⟨hal-04053984⟩
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