Association of adult mastocytosis with M541L in the transmembrane domain of KIT

Abstract

EditorMastocytosis is a disorder characterized by mast cell (MC) proliferation and accumulation within various organs, most commonly the skin. Multiple KIT mutations have been reported in patients with adult mastocytosis, but the potential association of specific KIT mutations with specific subtypes of mastocytosis remains to be clarified.We present the case of a 32-year-old caucasian woman who came to the Dermatology Department complaining of a 12-year history of multiple, generalized and reddish-brown macules and papules with positive Darier's sign. These lesions were more numerous in the trunk and limbs, and absent from face, palms and soles.She had no systemic symptoms and physical examination was unremarkable.Skin biopsy showed MC infiltrates in the dermis (Fig. 1), confirming the diagnosis of cutaneous mastocytosis.Full blood count, white blood cell differential and routine serum biochemistry tests were within normal range. Serum tryptase level was 17.9 ng ⁄ mL (normal: 0.1-11.4 ng ⁄ mL).The patient had a 46,XX karyotype. Abdominal ultrasound, PET scan and bone densitometry were all normal.Complete bone marrow study showed normal percentage of bone marrow MCs (BMMCs) (0.04%) which showed aberrant coexpression of CD25+, CD2+ and also CD33+, CD35+, CD45+, CD63+, CD69+ and CD59+. Analysis of coding exons 8, 9, 10, 11 and 17 of the KIT gene revealed the presence of a heterozygous substitution in exon 10, resulting in the substitution of leucine for methionine at codon 541 (M541L) (Fig. 2). The sequencing of KIT exon 10, using DNA extracted from oral mucosa cells, confirmed that this was a germline mutation.Human KIT is a protooncogene located at chromosome 4q12 that contains 21 exons, which encode a transmembrane receptor (kit) with tyrosine kinase (TK) activity. Binding of kit ligandstem cell factor (SCF) -to kit receptor is known to activate kit TK, which results in different biological effects depending on the activated cell. In MCs, these effects include, among others, cell proliferation and suppression of apoptosis. vating KIT mutations have been reported in patients with adult mastocytosis, but few are described in the transmembrane domain of KIT, 1 encoded by exon 10. In our patient, we detected a heterozygous substitution (germline mutation) in exon 10, resulting in the substitution of leucine for methionine at codon 541 (M541L). This mutation was described in general population, 4 in a family with piebaldism 5 and in two unrelated pairs of apparently identical twin children with mastocytosis. 6 To the best of our knowledge, however, this is the first time it is reported in an adult patient with mastocytosis. According to Foster et al., cells expressing M541L displayed a significantly heightened response to low levels of SCF,6 suggesting that these cells may have a proliferative and ⁄ or survival advantage. Although our patient had elevated serum tryptase levels, coexpression of both CD2 and CD25 by BMMCs and a KIT In conclusion, we would like to emphasize that this is the first time that M541L KIT m...

Impact of KIT exon 10 M541L allelic variant on the response to imatinib in aggressive fibromatosis: analysis of the desminib series by competitive allele specific Taqman PCR technology

“…The predictive value of a Single Nucleotide Polymorphism (SNP) has not been reported, even though several reports show that the KIT L541 variant may provide a positive signal in different diseases. Foster and Rocha independently reported the presence of KIT L541 in 5 patients with mastocytosis, in 2 pairs of twins (children) and in 1 adult, respectively [ 21 , 22 ]. Foster combined this clinical observation with in vitro analysis demonstrating that FDC-P1 cells transfected with KIT L541 showed an enhanced proliferative response, only to low levels of stem cell factor (SCF) (≤6.25 ng/ml), but did not confer factor independence.…”

Molecular Landscape and Clonal Evolution of Acute Mast Cell Leukemia: Case Study

“…During disease progression, we found no mutations in other genes associated with mastocytosis (ETNK1, EZH2, STAT5A) [18] or any other known KIT mutations, based on a pediatric review of 1747 cases [19]. Moreover, we did not find a polymorphism that resulted in the amino acid substitution, p.Met541Leu [5,6,20,21].…”

“…Other known variants are imatinib-sensitive, and they mainly carry mutations in the transmembrane domain of the protein. These variants are associated with a well-differentiated SM phenotype; for example, the p.Phe522Cys [3] and p.Met541Leu [4] variants may predispose to pediatric mastocytosis [5], or in adults, they may lead to an aberrant mast cell immunophenotype [6].…”

Ewing Sarcoma Developed at the Site of Previous Mast Cell Proliferation

“…Mutations involving exon 10, which involves the transmembrane domain, are rare and sporadically reported in adult mastocytosis. The M541L mutation on exon 10, present in the case reported here, was described in the literature in mast cell neoplasms for the first time in 2010 [ 20 ]. As far as we know, there are no previous reports describing the KIT M541L mutation involving specifically exon 10 in Ewing sarcoma.…”