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ACUTE MYELOID LEUKEMIA

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

Leukemia volume 36, pages 1585–1595 (2022)Cite this article

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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.

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Fig. 1: The cysteine biosynthesis pathway gene SLC7A11 is a poor prognostic factor in AML.
Fig. 2: Genetic and chemical inhibition of SLC7A11 has anti-leukemic activity.
Fig. 3: SLC7A11 expression is BRD4 dependent in AML.
Fig. 4: xCT inhibition induces global metabolic rewiring and ROS-mediated cell death.
Fig. 5: Sulfasalazine synergizes with anthracycline-based chemotherapies in AML.

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Acknowledgements

The authors thank Patrick Auberger and Didier Bouscary for helpful discussions, Jean-Michel Cayuela, Carole Albuquerque, Christophe Roumier, and Céline Decroocq from the Saint-Louis and Lille Tumor Banks for primary patient samples; Veronique Montcuquet, Nicolas Setterblad, Christelle Doliger, and Sophie Duchez from the Saint-Louis Research Institute Core Facility; Jean-Marc Massé and Alain Schmitt from the Electronic Microscopy Imaging Facility (‘PIME’) of Institut Cochin; and the technical staff from the DBA (Diagnostic Biologique Automatisé) platform of Saint-Louis Hospital. This work was also supported by the ATIP/AVENIR French research program (to AP), the EHA research grant for Non-Clinical Advanced Fellow (to AP), the Ligue Nationale Contre le Cancer (to AP), the Mairie de Paris Emergences grants (to AP), the INCA PLBIO program (PLBIO20-246, to AP), Fondation ARC (PGA1-RC20180206836 to RI), Association Laurette Fugain (ALF2020-01 to RI), Fondation Leucémie Espoir (to RI), Ligue contre le Cancer – Comité Ile-de-France (RS18/75-15 to RI), Association Princesse Margot (to RI), and the US National Cancer Institute (NCI) (NIH R35 CA210030 to KS). AP is a recipient of support from the ERC Starting program (758848) and supported by the St Louis Association for Leukemia Research. This work was also supported by the Commissariat à l’Energie Atomique et aux Energies Alternatives and the MetaboHUB infrastructure (ANR-11-INBS-0010 grant to FC and FF). This study was funded by grants from Fédération Leucémie Espoir and Ligue Contre le Cancer, Comité Ile-de-France (RS18/75-15) to RI.

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  1. These authors contributed equally: Alexandre Puissant, Raphael Itzykson.

Authors and Affiliations

  1. Université Paris Cité, Génomes, biologie cellulaire et thérapeutique U944, INSERM, CNRS, F-75010, Paris, France

    Bryann Pardieu, Justine Pasanisi, Frank Ling, Reinaldo Dal Bello, Justine Penneroux, Angela Su, Romane Joudinaud, Laureen Chat, Hsin Chieh Wu, Matthieu Duchmann, Gaetano Sodaro, Clémentine Chauvel, Loic Vasseur, Kim Pacchiardi, Yannis Belloucif, Marie-Charlotte Laiguillon, Camille Vaganay, Chaima Benaksas, Antoine Forget, Emmanuelle Clappier, Lionel Adès, Hugues de Thé, Nina Fenouille, Camille Lobry, Alexandre Puissant & Raphael Itzykson

  2. Département Hématologie et Immunologie, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, F-75010, Paris, France

    Reinaldo Dal Bello, Emmanuel Raffoux, Lionel Adès, Hervé Dombret & Raphael Itzykson

  3. Collège de France, Oncologie Cellulaire et Moléculaire, PSL University, INSERM UMR1050, CNRS UMR, 7241, Paris, France

    Hsin Chieh Wu & Hugues de Thé

  4. Laboratoire d’Hématologie, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, F-75010, Paris, France

    Clémentine Chauvel, Kim Pacchiardi & Emmanuelle Clappier

  5. Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé (DMTS), MetaboHUB, F-91191, Gif-sur-Yvette, France

    Florence A. Castelli & François Fenaille

  6. Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Cambridge, UK

    Eshwar Meduri & Brian J. Huntly

  7. Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA

    Gabriela Alexe & Kimberly Stegmaier

  8. The Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, MA, USA

    Gabriela Alexe, Kimberly Stegmaier & Hervé Dombret

  9. Université Paris Cité, Leukemia Transfer Lab, EA 3518, Institut de Recherche Saint-Louis, F-75010, Paris, France

    Jeannig Berrou, Thorsten Braun & Claude Gardin

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  1. Bryann Pardieu
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Contributions

RI and AP designed the study, performed analyses, and drafted the manuscript. HCW and HdT designed the PML−/− cell line. MCL, EM, BJH, and CL performed and analyzed ChIP-Seq experiments. FC and FF performed metabolomic experiments and primary analyses. GA performed ssGSEA and AVANA dependency analyses under the supervision of KS. BP designed and performed all other experiments with assistance from JP, FL, RdB, JP, AS, YB, RJ, LC, GS, CC, KP, CV, JB, CB, AF, and NF. TB, CG, ER, LA, and HD provided primary AML samples. LV MD and EC provided the molecular annotations for primary AML samples. All authors reviewed the manuscript and approved its final version.

Corresponding author

Correspondence to Raphael Itzykson.

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Competing interests

The authors have no conflicts of interest to disclose. RI has consulted for Abbvie, Amgen, BMS/Celgene, Daiichi-Sankyo, Jazz Pharma, Karyopharm, Novartis and Stemline Therapeutics, and received research funding from Novartis and Janssen, none of which is related to the present work. KS has consulted for Kronos Bio, Auron Therapeutics, and Astra-Zeneca on unrelated topics, receives grant funding from Novartis which did not fund this project, and holds stock options with Auron Therapeutics on unrelated topics.

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Pardieu, B., Pasanisi, J., Ling, F. et al. Cystine uptake inhibition potentiates front-line therapies in acute myeloid leukemia. Leukemia 36, 1585–1595 (2022). https://doi.org/10.1038/s41375-022-01573-6

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