Targeting oncogenic interleukin-7 receptor signalling with N-acetylcysteine in T cell acute lymphoblastic leukaemia.

Abstract

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.

• Authors: Marc R Mansour, Casie Reed, Amy R Eisenberg, Jen-Chieh Tseng, Jean-Claude Twizere, Sarah Daakour, Akinori Yoda, Scott J Rodig, Noa Tal, Chen Shochat, Alla Berezovskaya, Daniel J DeAngelo, Stephen E Sallan, David M Weinstock, Shai Izraeli, Andrew L Kung, Alex Kentsis, A Thomas Look
• Journal: British journal of haematology (Br J Haematol) Vol. 168 Issue 2 Pg. 230-8 (Jan 2015) ISSN: 1365-2141 [Electronic] England
• PMID: 25256574 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 John Wiley & Sons Ltd.

Chemical References

• RPSA protein, human
• Receptors, Laminin
• Ribosomal Proteins
• Acetylcysteine

Topics

• Acetylcysteine (pharmacology)
• Animals
• Apoptosis (physiology)
• Female
• Heterografts
• Humans
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Mutation
• Precursor T-Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, genetics, metabolism, pathology)
• Receptors, Laminin (genetics, metabolism)
• Ribosomal Proteins (genetics, metabolism)
• Signal Transduction