Reference Detail

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Blood	103	8	2004 Apr 15	3222-5	Blood

URL

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