Unique effects of KIT D816V in BaF3 cells: induction of cluster formation, histamine synthesis, and early mast cell differentiation antigens.
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.
Mayerhofer
Matthias
M
Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.
Gleixner
Karoline V
KV
Hoelbl
Andrea
A
Florian
Stefan
S
Hoermann
Gregor
G
Aichberger
Karl J
KJ
Bilban
Martin
M
Esterbauer
Harald
H
Krauth
Maria-Theresa
MT
Sperr
Wolfgang R
WR
Longley
Jack B
JB
Kralovics
Robert
R
Moriggl
Richard
R
Zappulla
Jacques
J
Liblau
Roland S
RS
Schwarzinger
Ilse
I
Sexl
Veronika
V
Sillaber
Christian
C
Valent
Peter
P
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
D000943:Antigens, Differentiation; D006632:Histamine; D019009:Proto-Oncogene Proteins c-kit