Back to Search
Start Over
Targeting oncogenic interleukin-7 receptor signalling with N-acetylcysteine in T cell acute lymphoblastic leukaemia.
- Source :
-
British journal of haematology [Br J Haematol] 2015 Jan; Vol. 168 (2), pp. 230-8. Date of Electronic Publication: 2014 Sep 26. - Publication Year :
- 2015
-
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.<br /> (© 2014 John Wiley & Sons Ltd.)
- Subjects :
- Animals
Apoptosis physiology
Female
Heterografts
Humans
Mice
Mice, Inbred NOD
Mice, SCID
Mutation
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma genetics
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma pathology
Receptors, Laminin genetics
Ribosomal Proteins genetics
Signal Transduction
Acetylcysteine pharmacology
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma drug therapy
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma metabolism
Receptors, Laminin metabolism
Ribosomal Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1365-2141
- Volume :
- 168
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- British journal of haematology
- Publication Type :
- Academic Journal
- Accession number :
- 25256574
- Full Text :
- https://doi.org/10.1111/bjh.13115