Activation of the KIT tyrosine kinase by somatic mutation has been documented in a number of human malignancies, including gastrointestinal stromal tumor (GIST), seminoma, acute myelogenous leukemia (AML), and mastocytosis.
CEACAM1 knockdown upregulated cell growth of HMC1.2 cells harboring KIT mutations detected in clinical mastocytosis, whereas downregulated the growth of TT cells harboring RET mutations detected in clinical MTCs.
Primary disorders causing constitutively hyperactivity of mast cells are called mastocytosis and are frequently due to a gain-of-function mutation of the KIT gene encoding the transmembrane tyrosine kinase receptor.
For those malignancies associated with KIT mutation or over-expression, imatinib offers a specific therapeutic option, yet it has no effect on D816V mutation commonly seen in sporadic mastocytosis.
ROSA(KITD816V) may provide a valuable tool for studying the pathogenesis of mastocytosis and should facilitate the development of novel drugs for treating SM patients.
These observations suggest that although activating c-KIT mutations are associated with mast cell growth, other genes probably play a role in the cause of mastocytosis.
Mastocytosis is associated with an activating mutation in the KIT oncoprotein (KITD816V) that results in autophosphorylation of the KIT receptor in a ligand-independent manner.
The use of allele-specific quantitative polymerase chain reaction to identify KITD816V in the peripheral blood of adults with mastocytosis has been reported to have value in the diagnosis, assessment of disease burden and management of this disease.
Complex karyotype and absence of mutation in the c-kit receptor in aggressive mastocytosis presenting with pelvic osteolysis, eosinophilia and brain damage.
The M541LKIT substitution (KIT(M541L)) has been described to be associated with pediatric mastocytosis, to enhance growth rate of the affected cells and to confer higher sensitivity to imatinib therapy.
Immunostaining with antibodies against tryptase, KIT, and CD25 and molecular analysis for detection of C-KIT point mutations were performed in approximately 550/4100 myelogenous malignancies including mastocytosis, almost all subtypes of myelodysplastic syndrome (MDS), myelodysplastic/myeloproliferative syndrome (MDS/MPD), MPD, and acute myeloid leukaemia (AML).
We generated a Cre/loxP-based bacterial artificial chromosome transgenic mouse model that allows conditional expression of a kit gene carrying the kitD814V mutation (the murine homolog of the most common mutation in human mastocytosis, kitD816V) driven by the kit promoter.
Our study thus supports a role for mast cells and D816V-KIT activity in IL-6 dysregulation in mastocytosis and provides insights into the intracellular mechanisms.
Acute myeloid leukemia with t(8;21)(q22;q22.1)/RUNX1-RUNX1T1 and KIT Exon 8 mutation is associated with characteristic mastocytosis and dismal outcomes.
Although the KITD816V mutation is typically found in adult-onset mastocytosis, it is less commonly seen in childhood-onset mastocytosis, and the frequency of KIT mutations in paediatric solitary mastocytoma is poorly documented.
The reason for this decreased sensitivity to TKIs is related to the resistance of the D816V variant of c-KIT, found in the majority of patients with mastocytosis.
We demonstrate for the first time that by using a sufficiently sensitive KITD816V mutation analysis, it is possible to detect the mutation in PB in nearly all adult mastocytosis patients.