Activating and dominant inactivating c-KITcatalytic domain mutations in distinct clinical forms of human mastocytosis

Abstract

Human mastocytosis is characterized by increased mast cells. It usually occurs as a sporadic disease that is often transient and limited in children and persistent or progressive in adults. The c-KIT protooncogene encodes KIT, a tyrosine kinase that is the receptor for mast cell growth factor. Because mutated KIT can transform cells, we examined c-KIT in skin lesions of 22 patients with sporadic mastocytosis and 3 patients with familial mastocytosis. All patients with adult sporadic mastocytosis had somatic c-KIT mutations in codon 816 causing substitution of valine for aspartate and spontaneous activation of mast cell growth factor receptor (P ‫؍‬ 0.0001). A subset of four pediatric onset cases with clinically unusual disease also had codon 816 activating mutations substituting valine, tyrosine, or phenylalanine for aspartate. Typical pediatric patients lacked 816 mutations, but limited sequencing showed three of six had a novel dominant inactivating mutation substituting lysine for glutamic acid in position 839, the site of a potential salt bridge that is highly conserved in receptor tyrosine kinases. No c-KIT mutations were found in the entire coding region of three patients with familial mastocytosis. We conclude that c-KIT somatic mutations substituting valine in position 816

Activation of mitogen activated protein kinase-Erk kinase (MEK) increases T cell immunoglobulin mucin domain-3 (TIM-3) transcription in human T lymphocytes and a human mast cell line

“…Therefore, it is plausible that MEK activation possibly occurs through a c-kit signaling pathway in HMC-1 cells, which synergistically up-regulates TGF-␤-induced TIM-3 transcription. Pathologically, the same c-kit mutations found in HMC-1 are observed in patients with mastocytosis (Buttner et al, 1998;Longley et al, 1999). Furthermore, elevation of the expression levels of SCF and TGF-␤ is observed in human synovium of rheumatoid arthritis as well as in a scleroderma mouse model, of which a common feature is mast cell hyperplasia (Olsson et al, 2001;Wang et al, 2005).…”

Target interaction profiling of midostaurin and its metabolites in neoplastic mast cells predicts distinct effects on activation and growth

“…In almost all patients, the bone marrow (BM) is affected (1)(2)(3)(4)(5). The transforming KIT mutation D816V is expressed in neoplastic cells in most patients (6)(7)(8)(9)(10).…”

Hotspot mutations in common oncogenes are infrequent in nasopharyngeal carcinoma

“…K558_V560del and V559I are juxtamembrane mutations located in exon 11 of KIT oncogene which have been observed in GISTs (43,44) and aggressive systemic mastocytosis (ASM), respectively (44). These two mutants showed spontaneous KIT phosphorylation (45) and could transform IL-3-dependent Ba/F3 cells into IL-3-independent growth in the absence of KIT ligand stem cell factor (SCF) (46). In contrast, KIT E839K was not spontaneously phosphorylated in response to exogenous SCF and thus lacked cell transforming ability (45).…”