Targeting oncogenic interleukin-7 receptor signalling with N-acetylcysteine in T cell acute lymphoblastic leukaemia

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

Research output: Contribution to journalArticlepeer-review

Abstract

Summary: 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.

Original languageEnglish
Pages (from-to)230-238
Number of pages9
JournalBritish Journal of Haematology
Volume168
Issue number2
DOIs
StatePublished - 1 Jan 2015
Externally publishedYes

Keywords

  • Acute leukaemia
  • T-cell lymphoma
  • Therapy

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