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Constitutively activating mutations of c-kit receptor tyrosine kinase
confer factor-independent growth and tumorigenicity of factor-dependent
hematopoietic cell lines
H Kitayama, Y Kanakura, T Furitsu, T Tsujimura, K Oritani, H Ikeda, H Sugahara, H Mitsui, Y Kanayama and Y Kitamura
Second Department of Internal Medicine, Osaka University Medical School,
Japan.
The c-kit receptor tyrosine kinase (KIT) is activated upon ligand binding,
thereby leading to a variety of signaling events that play a fundamental
role in hematopoiesis. In addition to ligand-dependent activation, we have
previously shown that KIT is constitutively activated in a
ligand-independent manner by two point mutations, Val- 559-->Gly (G559)
mutation in the juxtamembrane domain and Asp-814-->Val (V814) mutation
in the phosphotransferase domain. To investigate the biochemical
consequence and biologic significance of these mutations, retroviral
vectors encoding KITG559 or KITV814 were introduced into murine pro-B-type
Ba/F3 cells and myeloid FDC-P1 cells, both of which require interleukin-3
(IL-3) for their growth and survival. In the cells, KITG559 or KITV814 were
found to be constitutively phophorylated on tyrosine in the absence of stem
cell factor (SCF) that is a ligand for KIT. Chemical cross-linking analysis
showed that a substantial fraction of the phosphorylated KITG559 underwent
dimerization even in the absence of SCF, whereas the phosphorylated KITV814
did not, suggesting the distinct mechanisms underlying constitutive
activation of KIT by G559 and V814 mutations. Furthermore, the cells
expressing either KITG559 or KITV814 were found to show a
factor-independent growth, whereas the cells expressing wild-type KIT
(KITWT) proliferated in response to SCF as well as IL-3. Moreover,
subcutaneous injection of Ba/F3 cells expressing KITG559 or KITV814 into
nude mice resulted in production of large tumors at all sites of the
injection within 2 weeks, and all nude mice quickly succumbed to leukemia
and died. These results suggest that, although the mechanisms underlying
constitutive activation of KITG559 or KITV814 may be different, both of the
activating mutations have a function to induce a factor-independent and
tumorigenic phenotype. Also, the data of this study raise the possibility
that the constitutively activating mutations of c-kit may play a causal
role in development of hematologic malignancies.
Volume 85,
Issue 3,
pp. 790-798,
02/01/1995
Copyright © 1995 by The American Society of Hematology
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27(1):
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|
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|
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|
|
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59(6):
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|
|
|
|
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|
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107(9):
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|
|
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102(52):
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202(12):
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[Full Text]
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|
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|
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77(6):
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|
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|
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|
|
|
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|
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|
|
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|
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|
|
|
|
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102(4):
1474 - 1479.
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|
|
|
|
|
|
|
R. Shivakrupa, A. Bernstein, N. Watring, and D. Linnekin
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63(15):
4412 - 4419.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. R. Choi, H. Kim, H. J. Kang, N.-G. Kim, J. J. Kim, K.-S. Park, Y.-K. Paik, H. O. Kim, and H. Kim
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63(9):
2188 - 2193.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Sotlar, L. Escribano, O. Landt, S. Mohrle, S. Herrero, A. Torrelo, U. Lass, H.-P. Horny, and B. Bultmann
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162(3):
737 - 746.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Hashimoto, I. Matsumura, T. Tsujimura, D.-K. Kim, H. Ogihara, H. Ikeda, S. Ueda, M. Mizuki, H. Sugahara, H. Shibayama, et al.
Necessity of tyrosine 719 and phosphatidylinositol 3'-kinase-mediated signal pathway in constitutive activation and oncogenic potential of c-kit receptor tyrosine kinase with the Asp814Val mutation
Blood,
February 1, 2003;
101(3):
1094 - 1102.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. M. Irusta, Y. Luo, O. Bakht, C.-C. Lai, S. O. Smith, and D. DiMaio
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J. Biol. Chem.,
October 4, 2002;
277(41):
38627 - 38634.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. J. Frost, P. T. Ferrao, T. P. Hughes, and L. K. Ashman
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1(12):
1115 - 1124.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Zemke, B. Yamini, and V. Yuzbasiyan-Gurkan
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September 1, 2002;
39(5):
529 - 535.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Ueda, M. Mizuki, H. Ikeda, T. Tsujimura, I. Matsumura, K. Nakano, H. Daino, Z.-i. Honda, J. Sonoyama, H. Shibayama, et al.
Critical roles of c-Kit tyrosine residues 567 and 719 in stem cell factor-induced chemotaxis: contribution of src family kinase and PI3-kinase on calcium mobilization and cell migration
Blood,
May 1, 2002;
99(9):
3342 - 3349.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. C. Heinrich, C. D. Blanke, B. J. Druker, and C. L. Corless
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J. Clin. Oncol.,
March 15, 2002;
20(6):
1692 - 1703.
[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]
|
|
|
|
|
|
|
M. L. Taylor, J. Dastych, D. Sehgal, M. Sundstrom, G. Nilsson, C. Akin, R. G. Mage, and D. D. Metcalfe
The Kit-activating mutation D816V enhances stem cell factor-dependent chemotaxis
Blood,
August 15, 2001;
98(4):
1195 - 1199.
[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]
|
|
|
|
|
|
|
M. A. Morgan, O. Dolp, and C. W. M. Reuter
Cell-cycle-dependent activation of mitogen-activated protein kinase kinase (MEK-1/2) in myeloid leukemia cell lines and induction of growth inhibition and apoptosis by inhibitors of RAS signaling
Blood,
March 15, 2001;
97(6):
1823 - 1834.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Meshinchi, W. G. Woods, D. L. Stirewalt, D. A. Sweetser, J. D. Buckley, T. K. Tjoa, I. D. Bernstein, and J. P. Radich
Prevalence and prognostic significance of Flt3 internal tandem duplication in pediatric acute myeloid leukemia
Blood,
January 1, 2001;
97(1):
89 - 94.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. A. Bell, J. A. Tynan, K. C. Hart, A. N. Meyer, S. C. Robertson, and D. J. Donoghue
Rotational Coupling of the Transmembrane and Kinase Domains of the Neu Receptor Tyrosine Kinase
Mol. Biol. Cell,
October 1, 2000;
11(10):
3589 - 3599.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
K Sotlar, T Marafioti, H Griesser, J Theil, C Aepinus, R Jaussi, H Stein, P Valent, and H-P Horny
Detection of c-kit mutation Asp 816 to Val in microdissected bone marrow infiltrates in a case of systemic mastocytosis associated with chronic myelomonocytic leukaemia
Mol. Pathol.,
August 1, 2000;
53(4):
188 - 193.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
S. Xiao, J. G. McCarthy, J. C. Aster, and J. A. Fletcher
ZNF198-FGFR1 transforming activity depends on a novel proline-rich ZNF198 oligomerization domain
Blood,
July 15, 2000;
96(2):
699 - 704.
[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]
|
|
|
|
|
|
|
M. L. Lux, B. P. Rubin, T. L. Biase, C.-J. Chen, T. Maclure, G. Demetri, S. Xiao, S. Singer, C. D.M. Fletcher, and J. A. Fletcher
KIT Extracellular and Kinase Domain Mutations in Gastrointestinal Stromal Tumors
Am. J. Pathol.,
March 1, 2000;
156(3):
791 - 795.
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