Targeting oncogenic interleukin‐7 receptor signalling with N‐acetylcysteine in T cell acute lymphoblastic leukaemia. (26th September 2014)

• Record Type: Journal Article
• Authors: Mansour, Marc R.; Reed, Casie; Eisenberg, Amy R.; Tseng, Jen‐Chieh; Twizere, Jean‐Claude; Daakour, Sarah; Yoda, Akinori; Rodig, Scott J.; Tal, Noa; Shochat, Chen; Berezovskaya, Alla; DeAngelo, Daniel J.; Sallan, Stephen E.; Weinstock, David M.; Izraeli, Shai; Kung, Andrew L.; Kentsis, Alex; Look, A. Thomas
• Is Part Of: British journal of haematology. Volume 168:Number 2(2015:Jan.)
• Page Start: 230
• Page End: 238
• Publication Date: 2014-09-26
• Subjects: Hematology -- Periodicals; Blood -- Diseases -- Periodicals; 616.15
• DOI: 10.1111/bjh.13115
• Languages: English
• ISSNs: 0007-1048

Abstract

<abstract abstract-type="main" id="bjh13115-abs-0001"> <title>Summary</title> <p>Activating mutations of the interleukin‐7 receptor (<italic>IL7R</italic>) 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 <italic>N</italic>‐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 <italic>IL7R</italic>‐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 <italic>IL7R</italic>‐mutant construct containing a cysteine insertion. The apoptotic effects of NAC could be rescued in part by a constitutively active allele of <italic>STAT5</italic>. 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.</p> </abstract>