title: Unique effects of KIT D816V in BaF3 cells: induction of cluster formation, histamine synthesis, and early mast cell differentiation antigens.
abstract: Oncogenic tyrosine kinases (TK) usually convert growth factor-dependent cells to factor independence with autonomous proliferation. However, TK-driven neoplasms often are indolent and characterized by cell differentiation rather than proliferation. A prototype of an indolent TK-driven neoplasm is indolent systemic mastocytosis. We found that the D816V-mutated variant of KIT, a TK detectable in most patients with systemic mastocytosis, induces cluster formation and expression of several mast cell differentiation and adhesion Ags, including microphthalmia transcription factor, IL-4 receptor, histamine, CD63, and ICAM-1 in IL-3-dependent BaF3 cells. By contrast, wild-type KIT did not induce cluster formation or mast cell differentiation Ags. Additionally, KIT D816V, but not wild-type KIT, induced STAT5 activation in BaF3 cells. However, despite these intriguing effects, KIT D816V did not convert BaF3 cells to factor-independent proliferation. Correspondingly, BaF3 cells with conditional expression of KIT D816V did not form tumors in nude mice. Together, the biologic effects of KIT D816V in BaF3 cells match strikingly with the clinical course of indolent systemic mastocytosis and with our recently established transgenic mouse model, in which KIT D816V induces indolent mast cell accumulations but usually does not induce a malignant mast cell disease. Based on all these results, it is hypothesized that KIT D816V as a single hit may be sufficient to cause indolent systemic mastocytosis, whereas additional defects may be required to induce aggressive mast cell disorders.
authors.affiliation: Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.
authors.forename: Matthias
authors.initials: M
authors.lastname: Mayerhofer
authors.forename: Karoline V
authors.initials: KV
authors.lastname: Gleixner
authors.forename: Andrea
authors.initials: A
authors.lastname: Hoelbl
authors.forename: Stefan
authors.initials: S
authors.lastname: Florian
authors.forename: Gregor
authors.initials: G
authors.lastname: Hoermann
authors.forename: Karl J
authors.initials: KJ
authors.lastname: Aichberger
authors.forename: Martin
authors.initials: M
authors.lastname: Bilban
authors.forename: Harald
authors.initials: H
authors.lastname: Esterbauer
authors.forename: Maria-Theresa
authors.initials: MT
authors.lastname: Krauth
authors.forename: Wolfgang R
authors.initials: WR
authors.lastname: Sperr
authors.forename: Jack B
authors.initials: JB
authors.lastname: Longley
authors.forename: Robert
authors.initials: R
authors.lastname: Kralovics
authors.forename: Richard
authors.initials: R
authors.lastname: Moriggl
authors.forename: Jacques
authors.initials: J
authors.lastname: Zappulla
authors.forename: Roland S
authors.initials: RS
authors.lastname: Liblau
authors.forename: Ilse
authors.initials: I
authors.lastname: Schwarzinger
authors.forename: Veronika
authors.initials: V
authors.lastname: Sexl
authors.forename: Christian
authors.initials: C
authors.lastname: Sillaber
authors.forename: Peter
authors.initials: P
authors.lastname: Valent
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism*; D002454:Cell Differentiation; D002460:Cell Line; D020869:Gene Expression Profiling; D006632:Histamine / Q000096:biosynthesis*; D006801:Humans; D008407:Mast Cells / Q000166:cytology / Q000276:immunology / Q000502:physiology*; D034721:Mastocytosis, Systemic / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009154:Mutation; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000943:Antigens, Differentiation; D006632:Histamine; D019009:Proto-Oncogene Proteins c-kit