title: 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).
  
  
  CONCLUSIONS
  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.affiliation: Department for Companion Animals and Horses, Clinic for Internal Medicine and Infectious Diseases, University of Veterinary Medicine Vienna, Vienna, Austria.
authors.forename: E
authors.initials: E
authors.lastname: Hadzijusufovic
authors.forename: B
authors.initials: B
authors.lastname: Peter
authors.forename: H
authors.initials: H
authors.lastname: Herrmann
authors.forename: T
authors.initials: T
authors.lastname: Rülicke
authors.forename: S
authors.initials: S
authors.lastname: Cerny-Reiterer
authors.forename: K
authors.initials: K
authors.lastname: Schuch
authors.forename: L
authors.initials: L
authors.lastname: Kenner
authors.forename: T
authors.initials: T
authors.lastname: Thaiwong
authors.forename: V
authors.initials: V
authors.lastname: Yuzbasiyan-Gurkan
authors.forename: W F
authors.initials: WF
authors.lastname: Pickl
authors.forename: M
authors.initials: M
authors.lastname: Willmann
authors.forename: P
authors.initials: P
authors.lastname: Valent
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004285:Dogs; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation / Q000187:drug effects; D006636:Histamine Release; D016130:Immunophenotyping; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D034801:Mastocytoma / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009154:Mutation; D010641:Phenotype; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D017455:Receptors, IgE / Q000276:immunology / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D017455:Receptors, IgE; D019009:Proto-Oncogene Proteins c-kit; D053148:Caspase 3