The genetic basis of mast cell activation disease - looking through a glass darkly

Crit Rev Oncol Hematol. 2015 Feb;93(2):75-89. doi: 10.1016/j.critrevonc.2014.09.001. Epub 2014 Sep 28.


Within the last decade, and in particular since 2012, research has greatly extended our understanding of the molecular basis of systemic mast cell activation disease (MCAD). Initial studies demonstrated that somatic mutations in the tyrosine kinase KIT led to the establishment of a clonal mast cell population. Recent studies, in particular those involving next generation sequencing analyses of advanced systemic mastocytosis, have revealed mutations in additional genes. The respective genes encode proteins for various signaling pathways, epigenetic regulators, the RNA splicing machinery, and transcription factors. Although almost all of the detected mutations are somatic in nature, transgenerational transmission of MCAD appears to be quite common. However, the molecular mechanisms underlying genetic predestination, e.g. germline mutations and the contribution of epigenetic processes, still await identification. The aim of the present review is to present and discuss available genetic findings, and to outline the relationship between adult-onset systemic MCAD and childhood-onset mastocytosis, often termed cutaneous mastocytosis, on the basis of current genetic data. Finally, the implications of increased knowledge of the molecular basis of MCAD in terms of diagnostics and therapy are discussed.

Keywords: Germline mutations; Inheritance; Mast cell activation disease; Mast cell activation syndrome; Mast cell leukemia; Somatic mutations; Systemic mastocytosis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adaptive Immunity
  • Clone Cells
  • Epigenesis, Genetic
  • Gene Expression
  • Humans
  • Immunity, Innate
  • Leukemia, Mast-Cell / diagnosis
  • Leukemia, Mast-Cell / genetics*
  • Leukemia, Mast-Cell / immunology
  • Leukemia, Mast-Cell / pathology
  • Mast Cells / immunology
  • Mast Cells / pathology*
  • Mastocytosis, Cutaneous / diagnosis
  • Mastocytosis, Cutaneous / genetics*
  • Mastocytosis, Cutaneous / immunology
  • Mastocytosis, Cutaneous / pathology
  • Mastocytosis, Systemic / diagnosis
  • Mastocytosis, Systemic / genetics*
  • Mastocytosis, Systemic / immunology
  • Mastocytosis, Systemic / pathology
  • Mutation
  • Proto-Oncogene Proteins c-kit / genetics*
  • Proto-Oncogene Proteins c-kit / immunology
  • RNA Splicing
  • Signal Transduction
  • Transcription Factors / genetics
  • Transcription Factors / immunology


  • Transcription Factors
  • Proto-Oncogene Proteins c-kit