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NI ‐1: a novel canine mastocytoma model for studying drug resistance and I g ER ‐dependent mast cell activation
Author(s) -
Hadzijusufovic E.,
Peter B.,
Herrmann H.,
Rülicke T.,
CernyReiterer S.,
Schuch K.,
Kenner L.,
Thaiwong T.,
YuzbasiyanGurkan V.,
Pickl W. F.,
Willmann M.,
Valent P.
Publication year - 2012
Publication title -
allergy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.363
H-Index - 173
eISSN - 1398-9995
pISSN - 0105-4538
DOI - 10.1111/j.1398-9995.2012.02833.x
Subject(s) - mastocytoma , systemic mastocytosis , cancer research , tryptase , imatinib , microbiology and biotechnology , tyrosine kinase , dasatinib , mast cell , biology , chemistry , receptor , immunology , biochemistry , myeloid leukemia , tumor cells
Background Advanced mast cell ( MC ) disorders are characterized by uncontrolled growth of neoplastic MC in various organs, mediator‐related symptoms, and a poor prognosis. Kit mutations supposedly contribute to abnormal growth and drug resistance in these patients. Methods We established a novel canine mastocytoma cell line, NI ‐1, from a patient suffering from MC leukemia. Results NI ‐1 cells were found to form mastocytoma lesions in NOD / SCID IL ‐2 R gamma null mice and to harbor several homozygous Kit mutations, including missense mutations at nucleotides 107( C → T ) and 1187( A → G ), a 12‐bp duplication (nucleotide 1263), and a 12‐bp deletion (nucleotide 1550). NI ‐1 cells expressed several MC differentiation antigens, including tryptase, K it, and a functional I g E receptor. Compared to the C 2 mastocytoma cell line harboring a Kit exon 11 mutation, NI ‐1 cells were found to be less responsive against the K it tyrosine kinase inhibitors ( TKI ) masitinib and imatinib, but were even more sensitive against proliferation‐inhibitory effects of the mammalian target of rapamycin ( mTOR ) blocker RAD 001 and PI 3‐kinase/ mTOR blocker NVP ‐ BEZ 235. The K it‐targeting multikinase inhibitors PK C412 and dasatinib were also found to override TKI resistance in NI ‐1 cells, and produced growth inhibition with reasonable IC 50 values (<0.1 μM). Conclusion NI ‐1 may serve as a useful tool to investigate I g E ‐dependent reactions and mechanisms of abnormal growth and drug resistance in neoplastic MC in advanced mastocytosis.