KIT – Mastocytosis

Mastocytosis is a clonal mast cell disorder characterized by pathologic mast cell accumulation in skin and/or internal organs. Activating somatic mutations in the KIT proto-oncogene, most notably the D816V substitution, underlie aberrant mast cell proliferation and survival in mastocytosis (PMID:8605325).

Clinical genetic studies demonstrate that the KIT D816V variant is detected in approximately 85% of adult systemic mastocytosis cases and in a majority of pediatric onset mastocytosis, with additional rare activating mutations in exons 9, 11 and 13 (PMID:27310990). Founder and germline variants such as K509I have been reported in familial systemic mastocytosis, conferring sensitivity to tyrosine kinase inhibitors (PMID:25139846).

Variant spectrum is dominated by missense changes: c.2459A>T (p.Asp820Val) (historically D816V) accounts for the vast majority of cases. Exon 9 in-frame duplications (e.g., p.Ala502_Tyr503dup) and transmembrane mutations (p.Phe522Cys) occur in KIT-D816V–negative cases and predict imatinib responsiveness (PMID:15070706).

Functional evidence from murine W locus models establishes that loss-of-function c-kit alleles cause mast cell deficiency, while gain-of-function mutations drive mast cell hyperplasia. W/Wv mice lack mast cells, whereas c-kit D814Y (murine equivalent of human D816V) induces factor-independent growth and tumorigenicity in mast cell lines (PMID:1690623).

In vitro assays show that the D816V mutation enhances SCF-dependent chemotaxis of mast cell precursors, enriching D816V-positive cells in migratory fractions (PMID:11493470). Constitutive KIT activation via D816V also triggers persistent STAT3 and PI3K/Akt signaling, up-regulating BCL-xL and c-MYC to promote cytokine-independent survival (PMID:11369651).

No studies have refuted the pathogenic role of KIT activating mutations in mastocytosis. The preponderance of somatic D816V in independent cohorts, concordant functional data, and successful targeted therapy (imatinib, midostaurin) support a definitive gene-disease relationship.

Key Take-home: KIT activating mutations, especially c.2459A>T (p.Asp820Val), are a definitive molecular marker in mastocytosis, guiding diagnostic confirmation and selection of tyrosine kinase inhibitor therapy.

References

• Medicine • 2016 • Mastocytosis among elderly patients: A multicenter retrospective French study on 53 patients. PMID:27310990
• Blood • 1996 • A point mutation in the catalytic domain of c-kit induces growth factor independence, tumorigenicity, and differentiation of mast cells. PMID:8605325
• Ciba Foundation symposium • 1990 • The mouse W/c-kit locus. PMID:1690623
• Blood • 2001 • The Kit-activating mutation D816V enhances stem cell factor--dependent chemotaxis. PMID:11493470
• Blood • 2001 • Signal transducer and activator of transcription 3 activation is required for Asp(816) mutant c-Kit-mediated cytokine-independent survival and proliferation in human leukemia cells. PMID:11369651
• Blood • 2004 • A novel form of mastocytosis associated with a transmembrane c-kit mutation and response to imatinib. PMID:15070706

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