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A point mutation in the catalytic domain of c-kit induces growth factor
independence, tumorigenicity, and differentiation of mast cells
X Piao and A Bernstein
Program in Molecular Biology and Cancer, Samuel Lunenfeld Research
Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
The murine W and Steel loci encode the Kit receptor tyrosine kinase and its
ligand, Steel factor, respectively. Loss of function mutations at either
the W or Sl loci lead to a variety of pleiotropic developmental defects,
including mast cell deficiency and severe macrocytic anemia. In addition to
these loss-of-function mutations, gain-of-function mutations in c-kit,
leading to constitutive activation of the Kit receptor, have also been
identified in both rodent and human mastocytomas. In this study, we have
examined the transforming potential and biologic effects of a point
mutation that results in substitution of the aspartic acid at codon 814 in
the cytoplasmic kinase domain to tyrosine (D814Y) by introducing either
wild-type (Kit) or mutant KitD814Y (KDY) cDNA into an
interleukin-3-dependent mast cell line IC2. Stimulation of cells expressing
the wild-type Kit receptor (IC2/Kit) with Steel factor in vitro resulted in
a short-term growth response, whereas IC2/KDY cells were capable of
sustained proliferation in a ligand-independent manner. In addition,
expression of KDY resulted in the oncogenic transformation of IC2 cells, as
determined by colony formation in vitro in the absence of exogenous growth
factors and the formation of mastocytomas in vivo in syngeneic DBA/2 mice.
Surprisingly, KDY expression in IC2 cells triggered dramatic changes in
cell size and the extent of granulation. In addition, KDY induced the
expression of mouse mast cell protease-4 (MMCP-4) and MMCP-6. In contrast,
neither of these molecular or cellular changes was observed in IC2/Kit
cells treated with Steel factor. These results show that the D814Y mutation
in the cytoplasmic kinase domain of the Kit receptor induces
ligand-independent mast cell growth in vitro, tumorigenicity in vivo, and
mast cell differentiation.
Volume 87,
Issue 8,
pp. 3117-3123,
04/15/1996
Copyright © 1996 by The American Society of Hematology
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