NI-1: a novel canine mastocytoma model for studying drug resistance and IgER-dependent mast cell activation.
Allergy
; 67(7): 858-68, 2012 Jul.
Article
in En
| MEDLINE
| ID: mdl-22583069
ABSTRACT
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-2Rgamma(null) mice and to harbor several homozygous Kit mutations, including missense mutations at nucleotides 107(CâT) and 1187(AâG), a 12-bp duplication (nucleotide 1263), and a 12-bp deletion (nucleotide 1550). NI-1 cells expressed several MC differentiation antigens, including tryptase, Kit, and a functional IgE receptor. Compared to the C2 mastocytoma cell line harboring a Kit exon 11 mutation, NI-1 cells were found to be less responsive against the Kit tyrosine kinase inhibitors (TKI) masitinib and imatinib, but were even more sensitive against proliferation-inhibitory effects of the mammalian target of rapamycin (mTOR) blocker RAD001 and PI3-kinase/mTOR blocker NVP-BEZ235. The Kit-targeting multikinase inhibitors PKC412 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 IgE-dependent reactions and mechanisms of abnormal growth and drug resistance in neoplastic MC in advanced mastocytosis.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Receptors, IgE
/
Drug Resistance, Neoplasm
/
Mastocytoma
/
Mast Cells
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Allergy
Year:
2012
Document type:
Article
Affiliation country:
Austria