Title: Novel, activating KIT-N822I mutation in familial cutaneous mastocytosis
Authors: Wasag, Bartosz ×
Niedoszytko, Marek
Piskorz, Anna
Lange, Magdalena
Renke, Joanna
Jassem, Ewa
Biernat, Wojciech
Debiec-Rychter, Maria
Limon, Janusz #
Issue Date: Aug-2011
Publisher: Springer-Verlag
Series Title: Experimental Hematology vol:39 issue:8 pages:859-865
Abstract: OBJECTIVE: 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. MATERIALS AND METHODS: Blood, urine, and buccal swab specimens were collected from the family members. Cos-7 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. RESULTS: 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. CONCLUSIONS: 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.
ISSN: 0301-472X
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
Laboratory for Neurofibromatosis Research
Laboratory for Genetics of Malignant Disorders
× corresponding author
# (joint) last author

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