Activation of KIT modulates the function of tumor necrosis factor-related apoptosis-inducing ligand receptor (TRAIL-R) in mast cells

Allergy. 2015 Jul;70(7):764-74. doi: 10.1111/all.12612. Epub 2015 Apr 16.


Background: Mastocytosis is characterized by the accumulation of mast cells (MCs) associated with activating mutations of KIT. Tumor necrosis factor-related apoptosis-inducing ligand receptors (TRAIL-Rs) are preferentially expressed on neoplastic cells and induce the extrinsic apoptotic pathway. Recent studies reported on the expression of TRAIL-Rs and TRAIL-induced apoptosis in cultured human MCs, which depend on stem cell factor (SCF)-induced or constitutive KIT activation.

Material and methods: We sought to further define the impact of TRAIL-Rs on MCs in vivo and in vitro. Using Cre/loxP recombination, we generated mice with MC-specific and ubiquitous knockout of TRAIL-R. In these mice, anaphylaxis and numbers of MCs were investigated. We also explored the expression and function of TRAIL-Rs in cultured murine and human MCs upon activation of KIT. By conducting immunofluorescence staining, we analyzed the expression of TRAIL-Rs in MCs infiltrating the bone marrow of patients with mastocytosis.

Results: MC-specific deletion of TRAIL-R was associated with a slight, but significant increase in anaphylaxis. Numbers of MCs in MC-specific knockouts of TRAIL-R were comparable to controls. Whereas cultured IL-3-dependent murine MCs from wild-type mice were resistant to TRAIL-induced apoptosis, SCF-stimulated MCs underwent apoptosis in response to TRAIL. Interestingly, activating KIT mutations also promoted sensitivity to TRAIL-mediated apoptosis in human MCs. In line with these findings, MCs infiltrating the bone marrow of patients with mastocytosis expressed TRAIL-R1.

Conclusions: Activation of KIT regulates the function of TRAIL-Rs in MCs. TRAIL-R1 may represent an attractive diagnostic and therapeutic target in diseases associated with KIT mutations, such as mastocytosis.

Keywords: KIT; apoptosis; mast cells; mastocytosis; tumor necrosis factor-related apoptosis-inducing ligand receptor (TRAIL-R).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Bone Marrow / immunology
  • Bone Marrow / metabolism
  • Bone Marrow / pathology
  • Cell Count
  • Cell Survival / drug effects
  • Disease Models, Animal
  • Gene Expression Regulation
  • Humans
  • Mast Cells / immunology*
  • Mast Cells / metabolism*
  • Mastocytosis / genetics
  • Mastocytosis / immunology
  • Mastocytosis / metabolism
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Mutation
  • Proto-Oncogene Proteins c-kit / genetics
  • Proto-Oncogene Proteins c-kit / metabolism*
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / genetics
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism*
  • Stem Cell Factor / metabolism
  • Stem Cell Factor / pharmacology
  • TNF-Related Apoptosis-Inducing Ligand / metabolism
  • TNF-Related Apoptosis-Inducing Ligand / pharmacology


  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Stem Cell Factor
  • TNF-Related Apoptosis-Inducing Ligand
  • Proto-Oncogene Proteins c-kit