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


MeSH Major

  • Acetylcysteine
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
  • Receptors, Laminin
  • Ribosomal Proteins


  • 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.

publication date

  • January 2015



  • Academic Article



  • eng

PubMed Central ID

  • PMC4303513

Digital Object Identifier (DOI)

  • 10.1111/bjh.13115

PubMed ID

  • 25256574

Additional Document Info

start page

  • 230

end page

  • 8


  • 168


  • 2