Conflict of interest: none declared.
Experimental Dermatology •Original article
Distinct signalling pathways for mutated KIT(V560G) and KIT(D816V) in mastocytosis
Article first published online: 18 JUN 2013
© 2013 British Association of Dermatologists
Clinical and Experimental Dermatology
Volume 38, Issue 5, pages 538–544, July 2013
How to Cite
Chan, I. J., Kasprowicz, S. and Tharp, M. D. (2013), Distinct signalling pathways for mutated KIT(V560G) and KIT(D816V) in mastocytosis. Clinical and Experimental Dermatology, 38: 538–544. doi: 10.1111/ced.12000
- Issue published online: 18 JUN 2013
- Article first published online: 18 JUN 2013
- Accepted for publication 26 June 2012
Background. The activating mutations KIT(V560G) and KIT(D816V) are associated with mastocytosis. Thus, identifying and inhibiting the signalling pathways associated with mutated KIT gene offers a potentially important strategy for the treatment of mastocytosis.
Aim. To correlate KIT mutations with specific signalling pathways in human mast-cell lines using pathway inhibitors.
Methods. Human mast-cell (HMC) lines expressing KIT(V560G) (the cell line HMC-1) and KIT(V560G and D816V) (HMC-1.2) were treated with specific signalling pathway inhibitors for 1–5 days, and the inhibitory effects on growth were determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell-proliferation assay, western blotting and flow cytometry.
Results. Growth inhibitory assays and western blot analyses showed that the Janus kinase 3/signal transducer and activator of transcription (JAK3/STAT) pathway is the preferential signalling pathway for KIT(V560G), whereas the mechanistic target of rapamycin complex 1/4E-binding protein 1 (mTORC1/4E-BP1) pathway is preferentially linked to KIT(D816V). Inhibition of these critical signalling pathways results in programmed cell death.
Conclusions. KIT(V560G) and KIT(D816V) use different signalling pathways that promote mast-cell growth. Inhibitors of these specific pathways might be effective in treating mastocytosis.