Targeting oncogenic interleukin‐7 receptor signalling with N‐acetylcysteine in T cell acute lymphoblastic leukaemia |
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| Authors: | Marc R. Mansour Casie Reed Amy R. Eisenberg Jen‐Chieh Tseng Jean‐Claude Twizere Sarah Daakour Akinori Yoda Scott J. Rodig Noa Tal Chen Shochat Alla Berezovskaya Daniel J. DeAngelo Stephen E. Sallan David M. Weinstock Shai Izraeli Andrew L. Kung Alex Kentsis A. Thomas Look |
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| Affiliation: | 1. Department of Pediatric Oncology, Dana‐Farber Cancer Institute, Harvard Medical School, Boston, MA, USA;2. Department of Haematology, UCL Cancer Institute, University College London, London, UK;3. Molecular Pharmacology and Chemistry Program, Sloan‐Kettering Institute, Department of Pediatrics, Memorial Sloan‐Kettering Cancer Center, New York, NY, USA;4. Lurie Family Imaging Center, Dana‐Farber Cancer Institute, Harvard Medical School, Boston, MA, USA;5. Laboratory of Protein Signalling and Interactions, Interdisciplinary Cluster for Applied Genoproteomics (GIGA‐R), University of Liège, Sart‐Tilman, Belgium;6. Department of Medical Oncology, Dana‐Farber Cancer Institute, Harvard Medical School, Boston, MA, USA;7. Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA;8. Cancer Research Centre, Sheba Medical Centre, Tel Hashomer and Tel Aviv University Medical School, Tel Aviv, Israel;9. Migal‐Galilee Bio‐Technology Centre and Tel Hai Academic College, Tel Hai, Israel;10. Department of Pediatrics, Columbia University, New York, NY, USA;11. Division of Hematology/Oncology, Children's Hospital, Boston, MA, USA |
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| Abstract: | Activating mutations of the interleukin‐7 receptor (IL7R) occur in approximately 10% of patients with T cell acute lymphoblastic leukaemia (T‐ALL). Most mutations generate a cysteine at the transmembrane domain leading to receptor homodimerization through disulfide bond formation and ligand‐independent activation of STAT5. We hypothesized that the reducing agent N‐acetylcysteine (NAC), a well‐tolerated drug used widely in clinical practice to treat acetaminophen overdose, would reduce disulfide bond formation, and inhibit mutant IL7R‐mediated oncogenic signalling. We found that treatment with NAC disrupted IL7R homodimerization in IL7R‐mutant DND‐41 cells as assessed by non‐reducing Western blot, as well as in a luciferase complementation assay. NAC led to STAT5 dephosphorylation and cell apoptosis at clinically achievable concentrations in DND‐41 cells, and Ba/F3 cells transformed by an IL7R‐mutant construct containing a cysteine insertion. The apoptotic effects of NAC could be rescued in part by a constitutively active allele of STAT5. Despite using doses lower than those tolerated in humans, NAC treatment significantly inhibited the progression of human DND‐41 cells engrafted in immunodeficient mice. Thus, targeting leukaemogenic IL7R homodimerization with NAC offers a potentially effective and feasible therapeutic strategy that warrants testing in patients with T‐ALL. |
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| Keywords: | acute leukaemia T‐cell lymphoma therapy |
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