|
|
 Previous Article | Table of Contents | Next Article 
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
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
I. Bachelet, A. Munitz, B. Berent-Maoz, D. Mankuta, and F. Levi-Schaffer
Suppression of Normal and Malignant Kit Signaling by a Bispecific Antibody Linking Kit with CD300a
J. Immunol.,
May 1, 2008;
180(9):
6064 - 6069.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. P. Zappulla, P. Dubreuil, S. Desbois, S. Letard, N. B. Hamouda, M. Daeron, G. Delsol, M. Arock, and R. S. Liblau
Mastocytosis in mice expressing human Kit receptor with the activating Asp816Val mutation
J. Exp. Med.,
December 19, 2005;
202(12):
1635 - 1641.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Nakagawa, Y. Matsuno, H. Kunitoh, A. Maeshima, H. Asamura, and R. Tsuchiya
Immunohistochemical KIT (CD117) Expression in Thymic Epithelial Tumors
Chest,
July 1, 2005;
128(1):
140 - 144.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Jelacic and D. Linnekin
PKC{delta} plays opposite roles in growth mediated by wild-type Kit and an oncogenic Kit mutant
Blood,
March 1, 2005;
105(5):
1923 - 1929.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H.-B. Ruan, N. Zhang, and X. Gao
Identification of a Novel Point Mutation of Mouse Proto-Oncogene c-kit Through N-Ethyl-N-nitrosourea Mutagenesis
Genetics,
February 1, 2005;
169(2):
819 - 831.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Chiara, M.-J. Goumans, H. Forsberg, A. Ahgren, A. Rasola, P. Aspenstrom, C. Wernstedt, C. Hellberg, C.-H. Heldin, and R. Heuchel
A Gain of Function Mutation in the Activation Loop of Plateletderived Growth Factor {beta}-Receptor Deregulates Its Kinase Activity
J. Biol. Chem.,
October 8, 2004;
279(41):
42516 - 42527.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Pardanani and A. Tefferi
Imatinib targets other than bcr/abl and their clinical relevance in myeloid disorders
Blood,
October 1, 2004;
104(7):
1931 - 1939.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Shivakrupa, A. Bernstein, N. Watring, and D. Linnekin
Phosphatidylinositol 3'-Kinase Is Required for Growth of Mast Cells Expressing the Kit Catalytic Domain Mutant
Cancer Res.,
August 1, 2003;
63(15):
4412 - 4419.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Grundler, C. Thiede, C. Miething, C. Steudel, C. Peschel, and J. Duyster
Sensitivity toward tyrosine kinase inhibitors varies between different activating mutations of the FLT3 receptor
Blood,
July 15, 2003;
102(2):
646 - 651.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. J. Frost, P. T. Ferrao, T. P. Hughes, and L. K. Ashman
Juxtamembrane Mutant V560GKit Is More Sensitive to Imatinib (STI571) Compared with Wild-Type c-Kit Whereas the Kinase Domain Mutant D816VKit Is Resistant
Mol. Cancer Ther.,
October 1, 2002;
1(12):
1115 - 1124.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Scappini, F. Onida, H. M. Kantarjian, L. Dong, S. Verstovsek, M. J. Keating, and M. Beran
Effects of Signal Transduction Inhibitor 571 in Acute Myelogenous Leukemia Cells
Clin. Cancer Res.,
December 1, 2001;
7(12):
3884 - 3893.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Chian, S. Young, A. Danilkovitch-Miagkova, L. Ronnstrand, E. Leonard, P. Ferrao, L. Ashman, and D. Linnekin
Phosphatidylinositol 3 kinase contributes to the transformation of hematopoietic cells by the D816V c-Kit mutant
Blood,
September 1, 2001;
98(5):
1365 - 1373.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Z.-Q. Ning, J. Li, and R. J. Arceci
Signal transducer and activator of transcription 3 activation is required for Asp816 mutant c-Kit-mediated cytokine-independent survival and proliferation in human leukemia cells
Blood,
June 1, 2001;
97(11):
3559 - 3567.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Hongyo, T. Li, M. Syaifudin, R. Baskar, H. Ikeda, Y. Kanakura, K. Aozasa, and T. Nomura
Specific c-kit Mutations in Sinonasal Natural Killer/T-Cell Lymphoma in China and Japan
Cancer Res.,
May 1, 2000;
60(9):
2345 - 2347.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
S. GIORDANO, A. MAFFE, T. A. WILLIAMS, S. ARTIGIANI, P. GUAL, A. BARDELLI, C. BASILICO, P. MICHIELI, and P. M. COMOGLIO
Different point mutations in the met oncogene elicit distinct biological properties
FASEB J,
February 1, 2000;
14(2):
399 - 406.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
A. Beghini, P. Peterlongo, C. B. Ripamonti, L. Larizza, R. Cairoli, E. Morra, and C. Mecucci
C-kit mutations in core binding factor leukemias
Blood,
January 15, 2000;
95(2):
726 - 728.
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. J. Longley Jr., D. D. Metcalfe, M. Tharp, X. Wang, L. Tyrrell, S.-z. Lu, D. Heitjan, and Y. Ma
Activating and dominant inactivating c-KIT catalytic domain mutations in distinct clinical forms of human mastocytosis
PNAS,
February 16, 1999;
96(4):
1609 - 1614.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. LUCAS, W. KRUGLUGER, P. SAMORAPOOMPICHIT, R. GAMPERL, H. BEUG, O. FÖRSTER, and G. BOLTZ-NITULESCU
Self-renewal, maturation, and differentiation of the rat myelomonocytic hematopoietic stem cell
FASEB J,
February 1, 1999;
13(2):
263 - 272.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
L. H. McKinlay, M. J. Tymms, R. S. Thomas, A. Seth, S. Hasthorpe, P. J. Hertzog, and I. Kola
The Role of Ets-1 in Mast Cell Granulocyte-Macrophage Colony-Stimulating Factor Expression and Activation
J. Immunol.,
October 15, 1998;
161(8):
4098 - 4105.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Jeffers, L. Schmidt, N. Nakaigawa, C. P. Webb, G. Weirich, T. Kishida, B. Zbar, and G. F. Vande Woude
Activating mutations for the Met tyrosine kinase receptor in human cancer
PNAS,
October 14, 1997;
94(21):
11445 - 11450.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. C. Broudy
Stem Cell Factor and Hematopoiesis
Blood,
August 15, 1997;
90(4):
1345 - 1364.
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. J. Gonda and R. J. D'Andrea
Activating Mutations in Cytokine Receptors: Implications for Receptor Function and Role in Disease
Blood,
January 15, 1997;
89(2):
355 - 369.
[Full Text]
[PDF]
|
|
|
|
|
|
|
X. Piao, R. Paulson, P. van der Geer, T. Pawson, and A. Bernstein
Oncogenic mutation in the Kit receptor tyrosine kinase alters substrate specificity and induces degradation of the protein tyrosine phosphatase SHP-1
PNAS,
December 10, 1996;
93(25):
14665 - 14669.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
