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Targeting oncogenic interleukin‐7 receptor signalling with N ‐acetylcysteine in T cell acute lymphoblastic leukaemia
Author(s) -
Mansour Marc R.,
Reed Casie,
Eisenberg Amy R.,
Tseng JenChieh,
Twizere JeanClaude,
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
Publication year - 2015
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.13115
Subject(s) - interleukin 7 receptor , cancer research , receptor , acetylcysteine , apoptosis , chemistry , pharmacology , microbiology and biotechnology , biology , cytotoxic t cell , biochemistry , il 2 receptor , in vitro , antioxidant
Summary Activating mutations of the interleukin‐7 receptor ( IL 7R ) 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 STAT 5. 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 IL 7R‐mediated oncogenic signalling. We found that treatment with NAC disrupted IL 7R homodimerization in IL 7R ‐mutant DND ‐41 cells as assessed by non‐reducing Western blot, as well as in a luciferase complementation assay. NAC led to STAT 5 dephosphorylation and cell apoptosis at clinically achievable concentrations in DND ‐41 cells, and Ba/F3 cells transformed by an IL 7R ‐mutant construct containing a cysteine insertion. The apoptotic effects of NAC could be rescued in part by a constitutively active allele of STAT 5 . 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 IL 7R homodimerization with NAC offers a potentially effective and feasible therapeutic strategy that warrants testing in patients with T‐ ALL .