Identification of Activating c-kit Mutations in Adult-, but not in Childhood-Onset Indolent Mastocytosis: A Possible Explanation for Divergent Clinical Behavior

Abstract

Mastocytosis represents a mast cell proliferative disease that generally runs a benign clinical course, with spontaneous remissions mostly by puberty in childhood-onset disease, although rare forms, particularly in adult-onset disease, can be associated with (pre)malignant hematologic disorders and very rarely present as mast cell leukemia or malignant mastocytosis. Reasons for this divergent clinical behavior of childhood- versus adult-onset disease are unknown. Recently, two activating mutations in the intracellular domain of the proto-oncogene c-kit, which encodes a tyrosine kinase receptor for the mast cell growth factor stem cell factor, have been detected in the human leukemic mast cell line HMC-1. We have therefore studied lesional skin biopsies from patients with adult- and childhood-onset indolent mastocytosis for the presence of these codon 560 and 816 mutations. C-kit coding DNA sequences were amplified and analyzed by mutation-specific restriction analyses, and mutated polymerase chain reaction products were additionally cloned and sequenced. The codon 816 mutation was found in all six samples from adult patients, but not in any of the 11 specimens from children. In addition, the codon 560 mutation could be demonstrated for the first time in indolent mastocytosis, namely in two of four specimens from adult patients, but not in those from two children. These data thus provide a possible explanation for the divergent clinical behavior of adult- versus childhood-onset indolent mastocytosis, with the first being associated with an activating mutation, possibly as part of a neoplastic process, and the latter representing most likely a reactive process of an as yet unknown pathogenesis.

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).…”

Expression of Bcl-2 and Bcl-xL in Cutaneous and Bone Marrow Lesions of Mastocytosis

“…7 Written, informed consent was obtained from all patients and controls before biopsies were performed. The study was approved by the ethical committee of the Humboldt University, Berlin, Germany.…”

Systemic mastocytosis in adults: 2015 update on diagnosis, risk stratification, and management

“…Other less common (<5%) somatic KIT mutations identified in adult SM include V560G [30,31], D815K [32], D816Y [29,[32][33][34], insVI815-816 [29], D816F [32,34], D816H [35], and D820G [36]. Recent studies have confirmed that childhood-onset mastocytosis is also clearly clonal in nature, and is associated with germline or acquired activating KIT mutations [37][38][39].…”