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Ref Type

Journal Article

PMID

(21689725)

Authors

Wasag B, Niedoszytko M, Piskorz A, Lange M, Renke J, Jassem E, Biernat W, Debiec-Rychter M, Limon J

Title

Novel, activating KIT-N822I mutation in familial cutaneous mastocytosis.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Experimental hematology	39	8	2011 Aug	859-65.e2	Exp Hematol

URL

Abstract Text

We report the rare family in which cutaneous mastocytosis was diagnosed in the father and two children, with urticaria pigmentosa as the only manifestation of the disease. The diagnosis of mastocytosis in the father included bone marrow histopathological and cytological examinations and flow cytometry, and histopathological examination of the skin. In the children, tryptase measurement and skin histopathological examination were performed.Blood, urine, and buccal swab specimens were collected from the family members. HEK293T cells were transiently transfected with plasmids expressing KIT-WT and KIT-N882I. In addition, Ba/F3 cell lines expressing KIT-N822I, KIT-D816V, and KIT-V559D mutants were treated with imatinib and dasatinib. The effect of treatment on proliferation, survival, and signaling was determined.Germ-line KIT-N822I missense mutation was detected in the affected members of the family. Western blot analysis using HEK293T and Ba/F3 cells expressing KIT-N822I isoform showed that KIT-N822I constitutively activated KIT tyrosine phosphorylation. In vitro assays on KIT-N822I-expressing Ba/F3 cells confirmed that the N822I mutant is resistant to imatinib mesylate. In contrast, a high efficacy of dasatinib toward the KIT-N822I-expressing Ba/F3 cells was observed.We provided evidence that KIT p.N822I mutation has transforming potential and can cause a constitutive activation of KIT. In addition, we demonstrated that KIT-N822I is resistant to imatinib and sensitive to dasatinib. Finally, our findings support the hypothesis that not only KIT mutations but other additional genetic abnormalities are contributing to more advanced forms of the disease.

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Molecular Profile	Treatment Approach
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Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role
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Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
KIT	V559D	missense	gain of function	KIT V559D lies within the juxtamembrane domain (exon 11) of the Kit protein (PMID: 9438854). V559D confers a gain of function on Kit, as indicated by constitutive Kit phosphorylation, and is transforming in cell culture (PMID: 9438854, PMID: 21689725).
KIT	N822I	missense	gain of function	KIT N822I lies within the tyrosine kinase domain 2 of the Kit protein (PMID: 17555444). N822I results in constitutive Kit phosphorylation, is transforming in cell culture, and confers resistance to imatinib (PMID: 21689725).	Y

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Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
KIT N822I	Advanced Solid Tumor	sensitive	Dasatinib	Preclinical - Cell culture	Actionable	In a preclinical study, Sprycel (dasatinib) inhibited growth and induced apoptosis of transformed cells expressing KIT N822I in culture (PMID: 21689725).	21689725
KIT N822I	Advanced Solid Tumor	resistant	Imatinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing KIT N822I demonstrated resistance to Gleevec (imatinib) in culture (PMID: 21689725).	21689725
KIT V559D	Advanced Solid Tumor	sensitive	Imatinib	Preclinical - Cell culture	Actionable	In a preclinical study, Gleevec (imatinib) decreased KIT signaling, and inhibited growth and induced apoptosis of transformed cells expressing KIT V559D in culture (PMID: 21689725).	21689725
KIT V559D	Advanced Solid Tumor	sensitive	Dasatinib	Preclinical - Cell culture	Actionable	In a preclinical study, Sprycel (dasatinib) decreased KIT signaling, and inhibited growth and induced apoptosis of transformed cells expressing KIT V559D in culture (PMID: 21689725).	21689725

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