Article (Scientific journals)
Targeting oncogenic interleukin-7 receptor signalling with N-acetylcysteine in T cell acute lymphoblastic leukaemia.
Mansour, Marc R.; Reed, Casie; Eisenberg, Amy R. et al.
2015In British Journal of Haematology, 168 (2), p. 230-8
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Keywords :
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy/genetics/metabolism/pathology; Receptors, Laminin/genetics/metabolism; Ribosomal Proteins/genetics/metabolism; Signal Transduction; T-cell lymphoma; acute leukaemia; therapy
Abstract :
[en] 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.
Disciplines :
Hematology
Author, co-author :
Mansour, Marc R.
Reed, Casie
Eisenberg, Amy R.
Tseng, Jen-Chieh
Twizere, Jean-Claude  ;  Université de Liège > Agronomie, Bio-ingénierie et Chimie (AgroBioChem) > Biologie cell. et moléc.
Daakour, Sarah ;  Université de Liège > Agronomie, Bio-ingénierie et Chimie (AgroBioChem) > Biologie cell. et moléc.
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
More authors (8 more) Less
Language :
English
Title :
Targeting oncogenic interleukin-7 receptor signalling with N-acetylcysteine in T cell acute lymphoblastic leukaemia.
Publication date :
2015
Journal title :
British Journal of Haematology
ISSN :
0007-1048
eISSN :
1365-2141
Publisher :
Wiley, Oxford, United Kingdom
Volume :
168
Issue :
2
Pages :
230-8
Peer reviewed :
Peer Reviewed verified by ORBi
Commentary :
(c) 2014 John Wiley & Sons Ltd.
Available on ORBi :
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