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Ref Type Journal Article
PMID (15070706)
Authors Akin C, Fumo G, Yavuz AS, Lipsky PE, Neckers L, Metcalfe DD
Title A novel form of mastocytosis associated with a transmembrane c-kit mutation and response to imatinib.
Abstract Text Mutational analysis of the c-kit gene in a patient with a previously undescribed variant of mast cell disease revealed a germline mutation, Phe522Cys, within the transmembrane portion of the Kit receptor protein. Transfection experiments revealed that the mutation caused ligand-independent autophosphorylation of Kit, which was inhibited by the tyrosine kinase inhibitor imatinib mesylate. The patient's bone marrow biopsy and aspirate displayed unique pathologic features with the presence of excessive numbers of mature-appearing mast cells and absence of aberrant mast cell surface expression of CD2, CD25, and CD35. Therapy with imatinib mesylate resulted in a dramatic improvement in mast cell burden and clinical symptoms. These results highlight the significance of the transmembrane region of Kit in activation of the molecule and its importance in mast cell development and suggest a role for screening for transmembrane c-kit mutations in patients with mastocytosis in association with the decision to use imatinib mesylate.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
KIT F522C missense gain of function - predicted KIT F522C lies within the transmembrane domain of the Kit protein (PMID: 15070706). F522C results in ligand independent autophosphorylation of Kit in cell culture (PMID: 15070706), and therefore, is predicted to lead to a gain of Kit protein function.
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KIT F522C systemic mastocytosis sensitive Imatinib Case Reports/Case Series Actionable In a clinical case study, Gleevec (imatinib) treatment resulted in symptom and pathologic improvements in a patient with systemic mastocytosis harboring germline KIT F522C and inhibited growth of primary bone marrow cells derived from the patient in culture (PMID: 15070706). 15070706