Activity of Dasatinib Against Novel KIT-N822I Mutation In Familial Cutaneous Mastocytosis

In contrast to mastocytosis associated with somatic KIT mutations, the accounts of familial forms of mastocytosis with KIT germline mutations are extremely rare. We report the family that met the WHO criteria for cutaneous mastocytosis, which was diagnosed in the father and two children.

The clinical follow-up of mastocytosis in the father included bone marrow histopatological/cytological examinations and flow cytometry, and histopatological examination of the skin. In children tryptase measurement and skin histopatological examination was performed. The father and children presented with urticaria pigmentosa as the only manifestation of the disease. Blood, urine and buccal swabs specimens were collected from the family members. Molecular analysis of the KIT coding sequence revealed a novel missense mutation (p.N822I) in the affected members of the family.

Ba/F3 cell lines expressing KIT-N822I, KIT-D816V and KIT-V559D mutants were treated with different concentrations of imatinib and dasatinib. The effect of treatment on proliferation, survival, and signaling was determined. In addition, Cos-7 cells were transiently transfected with plasmids expressing KIT-WT and KIT-N882I.

By in vitro assays, both imatinib and dasatinib exhibited a high efficacy toward the control, imatinib-sensitive KIT-V559D mutant. In contrast, only dasatinib potently inhibited the KIT-N822I and control, imatinib-resistant KIT-D816V isoform with an IC50 value of 68 nmol/L and 77nmol/L, respectively. Finally, experiments with Cos-7 cells showed that on the contrary to KIT-WT the KIT-N822I mutation constitutively activated KIT tyrosine phosphorylation.

In summary, we proved that novel germline KIT mutation (p.N822I) has transforming potential and cause a constitutive activation of KIT. Moreover, we demonstrated that treatment with dasatinib may provide a therapeutic alternative for patients with mastocytosis whose carry imatinib-resistant KIT mutant isoforms.

No relevant conflicts of interest to declare.