Reference Detail

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 Experimental hematology
Vol 39
Issue 8
Date 2011 Aug
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
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Therapy Description
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
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
V559D missense gain of function KIT V559D lies within the juxtamembrane domain 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).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KIT V559D Advanced Solid Tumor sensitive Imatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT V559D were sensitive to Gleevec (imatinib), demonstrating decreased cell proliferation in culture and inhibition of Kit, Erk1/2, and Stat3 phosphorylation (PMID: 24205792). 24205792
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 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 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 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