Clinical Information

Systemic mastocytosis is a hematopoietic neoplasm that can be included in the general category of chronic myeloproliferative disorders (CMPD). These neoplasms are characterized by excessive proliferation of one or more myeloid lineages, with cells filling the bone marrow and populating other hematopoietic sites. In systemic mastocytosis, mast cell proliferation is the defining feature, although other myeloid lineages and B cells are frequently part of the neoplastic clone.

Function-altering point alterations in KIT, a gene coding for a membrane receptor tyrosine kinase, have been found in myeloid lineage cells in the majority of systemic mastocytosis cases. The most common KIT alteration is an adenine to thymine base substitution (A>T) at nucleotide position 2447, which results in an aspartic acid to valine change in the protein (Asp816Val). Much less frequently, other alterations at this same location are found, and occasional cases with alterations at other locations have also been reported. Variations at codon 816 are believed to alter the protein such that it is in a constitutively activated state. The main downstream effect of KIT activation is cell proliferation.

Detection of a variant at codon 816 is included as one of the minor diagnostic criteria for systemic mastocytosis in the World Health Organization classification system for hematopoietic neoplasms and is also of therapeutic relevance, as it confers resistance to imatinib, a drug commonly used to treat CMPD. It is now clear that individual mast cell neoplasms are variable with respect to the number of cell lineages containing the variant; some having positivity only in mast cells and others having positivity in additional myeloid and even lymphoid lineages. The alteration has not been reported in normal tissues.