Targeting oncogenic interleukin-7 receptor signalling with N-acetylcysteine in T cell acute lymphoblastic leukaemia Journal Article
| Authors: | Mansour, M. R.; Reed, C.; Eisenberg, A. R.; Tseng, J. C.; Twizere, J. C.; Daakour, S.; Yoda, A.; Rodig, S. J.; Tal, N.; Shochat, C.; Berezovskaya, A.; DeAngelo, D. J.; Sallan, S. E.; Weinstock, D. M.; Izraeli, S.; Kung, A. L.; Kentsis, A.; Look, A. T. |
| Article Title: | Targeting oncogenic interleukin-7 receptor signalling with N-acetylcysteine in T cell acute lymphoblastic leukaemia |
| 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. © 2014 John Wiley & Sons Ltd. |
| Keywords: | signal transduction; controlled study; human cell; cancer growth; nonhuman; polymerase chain reaction; mouse; cell viability; cell survival; apoptosis; animal experiment; animal model; gene frequency; in vivo study; in vitro study; acute lymphoblastic leukemia; molecular cloning; western blotting; dimerization; drug bioavailability; drug metabolism; protein dephosphorylation; drug half life; t-cell lymphoma; t cell leukemia; therapy; interleukin 7 receptor; acetylcysteine; acute leukaemia; human; female; priority journal; article |
| Journal Title: | British Journal of Haematology |
| Volume: | 168 |
| Issue: | 2 |
| ISSN: | 0007-1048 |
| Publisher: | John Wiley & Sons |
| Date Published: | 2015-01-01 |
| Start Page: | 230 |
| End Page: | 238 |
| Language: | English |
| DOI: | 10.1111/bjh.13115 |
| PROVIDER: | scopus |
| PMCID: | PMC4303513 |
| PUBMED: | 25256574 |
| DOI/URL: | |
| Notes: | Export Date: 2 April 2015 -- Source: Scopus |
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