NI-1: a novel canine mastocytoma model for studying drug resistance and IgER-dependent mast cell activation.

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(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, 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.

• Authors: E Hadzijusufovic, B Peter, H Herrmann, T Rülicke, S Cerny-Reiterer, K Schuch, L Kenner, T Thaiwong, V Yuzbasiyan-Gurkan, W F Pickl, M Willmann, P Valent
• Journal: Allergy (Allergy) Vol. 67 Issue 7 Pg. 858-68 (Jul 2012) ISSN: 1398-9995 [Electronic] Denmark
• PMID: 22583069 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2012 John Wiley & Sons A/S.

Chemical References

• Antineoplastic Agents
• Receptors, IgE
• Proto-Oncogene Proteins c-kit
• Caspase 3

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Caspase 3 (metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dogs
• Drug Resistance, Neoplasm
• Enzyme Activation (drug effects)
• Histamine Release
• Immunophenotyping
• Male
• Mast Cells (drug effects, metabolism, pathology)
• Mastocytoma (genetics, immunology, metabolism)
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Mutation
• Phenotype
• Proto-Oncogene Proteins c-kit (genetics)
• Receptors, IgE (immunology, metabolism)