• Open Access

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

Authors

  • E. Hadzijusufovic,

    1. Department for Companion Animals and Horses, Clinic for Internal Medicine and Infectious Diseases, University of Veterinary Medicine Vienna, Vienna, Austria
    2. Division of Hematology & Hemostaseology, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria
    3. Ludwig Boltzmann Cluster Oncology, Vienna, Austria
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  • B. Peter,

    1. Department for Companion Animals and Horses, Clinic for Internal Medicine and Infectious Diseases, University of Veterinary Medicine Vienna, Vienna, Austria
    2. Division of Hematology & Hemostaseology, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria
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  • H. Herrmann,

    1. Ludwig Boltzmann Cluster Oncology, Vienna, Austria
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  • T. Rülicke,

    1. Institute of Laboratory Animal Science, University of Veterinary Medicine Vienna, Vienna, Austria
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  • S. Cerny-Reiterer,

    1. Division of Hematology & Hemostaseology, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria
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  • K. Schuch,

    1. Institute of Immunology, Medical University of Vienna, Vienna, Austria
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  • L. Kenner,

    1. Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria
    2. Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria
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  • T. Thaiwong,

    1. Comparative Medicine and Integrative Biology Program, Michigan State University, East Lansing, MI, USA
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  • V. Yuzbasiyan-Gurkan,

    1. Comparative Medicine and Integrative Biology Program, Michigan State University, East Lansing, MI, USA
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  • W. F. Pickl,

    1. Institute of Immunology, Medical University of Vienna, Vienna, Austria
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  • M. Willmann,

    Corresponding author
    • Department for Companion Animals and Horses, Clinic for Internal Medicine and Infectious Diseases, University of Veterinary Medicine Vienna, Vienna, Austria
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  • P. Valent

    1. Division of Hematology & Hemostaseology, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria
    2. Ludwig Boltzmann Cluster Oncology, Vienna, Austria
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Correspondence

Michael Willmann, Department for Companion Animals and Horses, Clinic of Internal Medicine and Infectious Diseases, University of Veterinary Medicine, Veterinaerplatz 1, A-1210 Vienna, Austria.

Tel.: +43 1 25077 6870

Fax: +43 1 25077 5799

E-mail: michael.willmann@vetmeduni.ac.at

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-2Rgammanull 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 IC50 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.

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