title: Targeting oncogenic interleukin-7 receptor signalling with N-acetylcysteine in T cell acute lymphoblastic leukaemia.
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.
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Department of Haematology, UCL Cancer Institute, University College London, London, UK.
authors.forename: Marc R
authors.initials: MR
authors.lastname: Mansour
authors.forename: Casie
authors.initials: C
authors.lastname: Reed
authors.forename: Amy R
authors.initials: AR
authors.lastname: Eisenberg
authors.forename: Jen-Chieh
authors.initials: JC
authors.lastname: Tseng
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Twizere
authors.forename: Sarah
authors.initials: S
authors.lastname: Daakour
authors.forename: Akinori
authors.initials: A
authors.lastname: Yoda
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Rodig
authors.forename: Noa
authors.initials: N
authors.lastname: Tal
authors.forename: Chen
authors.initials: C
authors.lastname: Shochat
authors.forename: Alla
authors.initials: A
authors.lastname: Berezovskaya
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: DeAngelo
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Sallan
authors.forename: David M
authors.initials: DM
authors.lastname: Weinstock
authors.forename: Shai
authors.initials: S
authors.lastname: Izraeli
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Kung
authors.forename: Alex
authors.initials: A
authors.lastname: Kentsis
authors.forename: A Thomas
authors.initials: AT
authors.lastname: Look
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D005260:Female; D064593:Heterografts; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009154:Mutation; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017474:Receptors, Laminin / Q000235:genetics / Q000378:metabolism*; D012269:Ribosomal Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C510624:RPSA protein, human; D017474:Receptors, Laminin; D012269:Ribosomal Proteins; D000111:Acetylcysteine
keywords: T-cell lymphoma; acute leukaemia; therapy