Aggressive systemic mastocytosis (ASM) is a very rare form of mast cell
neoplasm that does not benefit from conventional
chemotherapy. The majority of adult mast cell
neoplasms and
gastrointestinal stromal tumors (GISTs) have mutations in the proto-oncogene c-kit, which encodes the KIT
receptor tyrosine kinase. The c-kit gene mutations are generally confined to the
tyrosine kinase II domain in mast cell
neoplasms, but are often observed at the juxtamembrane domain in GISTs. We found a case of ASM with a juxtamembrane-type mutation, Val559Ile, and in this report the mutation was characterized through transfection of the mutated c-kit
cDNA into human embryonic kidney cells. Phosphorylation of KIT and its possible downstream signaling molecules were examined in the presence or absence of
imatinib, a selective
tyrosine kinase inhibitor.
Ligand-independent autophosphorylation was observed in the mutant KIT with Val559Ile as well as that with Val559Asp, as found in GISTs.
Imatinib, at a concentration of 10 microM, inhibited autophosphorylation of the mutant KIT with Val559Asp, but not that with the Val559Ile. Phosphorylation of MAPK and STAT5 was also inhibited by
imatinib at the same concentration, in cells expressing Val559Asp but not in those expressing Val559Ile. These results suggest that different mutations, even at the same
codon, in juxtamembrane domain of the c-kit gene show different inhibitory effects of
imatinib, and that patients with GISTs or mast cell
neoplasms possessing this Val559Ile mutation are resistant to
imatinib therapy.