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Pathogenesis
Cellular Effectors and Regulators of Allergic Reactions
Int Arch Allergy Immunol 1995;107:54-56
Departments of
Pathology, and
Internal Medicine II,
Osaka University Medical School,
Osaka, Japan
Key Words
Mast cells
c-kit
Stem cell factor
Basophils
Mastocytoma
Regulation of Development,
Survival and Neoplastic Growth
of Mast Cells through the c
Receptor
Abstract
Signaling through the c-kit receptor tyrosine kinase (Kit) is essential for devel­
opment and survival of mast cells but not of basophils. Moreover, we recently
found an activation mutation of Kit in several tumor mast cell lines.
Development of Mast Cells and Basophils
All connective-tissue-type mast cells (CTMCs), mucosal-type mast cells (MMCs) and basophils are offspring of
the multipotential hematopoietic stem cell [1]. However, de­
velopmental processes o f mast cells (CTMCs and MMCs)
and basophils are different. Basophils complete their differ­
entiation within the bone marrow, but mast cell precursors
leave the bone marrow, invade connective or mucosal tissue,
proliferate and differentiate into CTMCs or MMCs [1].
We recently studied the kinetics of mast cell precursors
after infection of Nipposti-ongyli<s brasiliensis (NB). Mast­
cell precursors were defined as cells that produced mast cell
colonies (Mast-CFUs) in the methylcellulose culture con­
taining interleukin (IL)-3 and stem cell factor (SCF) [2].
The concentration of Mast-CFUs did not change in the bone
marrow after NB infection. The concentration o f MastCFUs in the peripheral blood o f+/+ rats dropped to one fifth
of preinfection levels 1 week after NB infection. In contrast,
the concentration of Mast-CFUs in the small intestine in­
creased 6-fold. Moreover, the proportion of Mast-CFUs in S
phase of the cell cycle remained low in the marrow and
blood, but increased significantly in the small intestine. NB
infection appeared to induce the invasion of Mast-CFUs
from the peripheral blood into the small intestine and their
proliferation after the invasion [2].
The mechanism regulating development differs among
CTMCs, MMCs and basophils. We investigated the differ­
ence using Ws/Ws rats with deficient activity of the c-kit re­
ceptor tyrosine kinase (Kit) [3, 4]. When Ws/Ws, nude athymic, and +/+ rats were infected with NB, the number of
basophils increased 50-fold in the peripheral blood of Ws/
Ws and +/+ rats but did not increase in that of nude rats [5].
Immature basophils increased 10-fold in the bone marrow
of Ws/Ws and +/+ rats but did not increase in that of nude
rats. This result confirms that T-cell-derived cytokines are
essential for the augmented production of basophils and
suggested that stimulation via Kit may not be necessary for
the augmented production [5].
Although mast cells did not develop in the skin of NBinfected Ws/Ws rats, a significant number of mast cells de­
veloped in the jejunum. These mast cells had the MMC pro­
tease phenotype [rat mast cell protease (RMCP) 1 /I f ] and
lacked heparin because they were not stained with berberine
( orrespondence to: Dr. Yukihiko Kitamura
Department of Pathology
Osaka University Medical School
Yamada-oka 2-2. Suita
Osaka 565 (Japan)
€> 1995 S. Kargcr AG, Basel
mix 2438 95 1073 0054
$8.00/0
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Yukihiko Kitamura8
Tohru Tsujimuraa
Tomoko Jippo*
Tsutomu Kasugai'
Yuzuru Kanakurab
sulfate. However, the number of MMCs and the serum con­
centration of RMCP II in NB-infectd Ws/Ws rats were only
13 and 7%, respectively, of those of NB-infected +/+ rats
[6]. These results indicate that the need for the stimulus
through the c-kit receptor appears to be greater in the devel­
opment of CTMCs than in the development of MMCs.
Survival of Mast Cells
W'h is a mutant at the c-kit (IV) locus of mice, but no sig­
nificant abnormalities are found in the coding region of the
Wsh allele [7]. Since cultured mast cells derived from the
spleen of Wsl/W sh mice did not express c-kit mRNA, we
studied the interrelation between the number of mast cells
and the magnitude of c-kit mRNA expression in the skin of
Wsl/W 'h mice of various ages [8], The number of mast cells
in the skin of Wsh/W 'h embryos was 40% that of control +/+
embryos, but the number o f mast cells decreased exponen­
tially after birth, dropping to 6 and 0.6% that of +/+ mice at
days 60 and 150 after birth, respectively. A weak but appar­
ent c-kit mRNA signal was detectable in the skin of fV'VlV'1'
embryos by RNase protection assay but not in the skin of
5-day-old Wsh/W sh mice. The number of c-kit protein-con­
taining mast cells was significantly greater in the skin of W*h
/W sh embryos than in the skin of 5-day-old Wsh/W sh mice.
The abolishment of c-kit mRNA expression appeared to be
specific, because the mRNA expression of mast cell carboxypeptidase A (a mast-cell-specific protease) but not of ckit was detectable by in situ hybridization in the skin mast
cells of 5-day-old w sh/W sh mice. Taken together, the expres­
sion of c-kit mRNA was abolished first, then the content of
c-kit protein dropped to undetectable levels and then the
mast cells themselves disappeared [8], This clearly indi­
cates the essential role of the SCF-K.it system for the surviv­
al of mast cells.
of the two mutations are completely conserved in all mouse,
rat and human Kits. Tsujimura et al. [10] found the corre­
sponding mutation in the P-815 mouse mastocytoma cell
linc(Asp814 to Tyr)and in the RBL-2H3 rat mast cell leuke­
mia cell line (Asp8l7 to Tyr). Both P-815 and RBL-2H3
cells showed constitutive activation of Kit without the addi­
tion of SCF.
In order to investigate the biological significance of
these mutations, the retroviral vector encoding a mutant Kit
(Kit-Val814) was introduced into the murine Ba/F3 pro-B
cell line, FDC-P1 myeloid cell line, and IC-2 mast cell line,
all of which require IL-3 for their growth and survival [11],
In these transfected cells, Kit-Val814 was constitutively
phosphorylated on tyrosine in the absence of SCF. The cells
expressing Kit-Val814 showed factor-independent growth,
whereas the cells expressing wild-type Kit proliferated in
response to SCF as well as IL-3. Subcutaneous injection of
Ba/F3 cells expressing Kit-Val814 into nude athymic mice
resulted in production of large tumors at all injection sites,
and all nude mice quickly succumbed to leukemia and died
[11], Moreover, we produced transgenic mice with the mu­
tant c-kit gene encoding Kit-Val814; leukemia developed in
three of them. There is a possibility that this c-kit mutation
has induced mast cell tumors in humans, mice and rats.
Activation Mutation of c-kit and Mast Cell Tumors
55
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Binding of SCF activates Kit and leads to autophospho­
rylation of Kit on tyrosine and to association of Kit with
substrates such as phosphatidylinositol 3-kinase (PI3K). In
a human mast cell leukemia cell line, HMC-1, Kit was constitutively phosphorylated on tyrosine, activated, and asso­
ciated with PI3K without the addition of SCF. Furitsu et al.
[9] found that the c-kit gene of HMC-1 cells was composed
of a normal, wild-type allele and a mutant allele with point
mutations resulting in amino acid substitutions of Val560 to
Gly and Asp816 to Val. Amino acid sequences in the regions
1 Kitamura Y: Heterogeneity o f mast cells and
phenotypic change between subpopulations.
Annu Rev Immunol 1989;7:59-76.
2 Kasugai T.Tei H ,Okada M. I lirota S. Morimoto
M. Yamada M, Nakama A. Arizono N. Kitam­
ura Y: Infection of Nipposlrongylus brasiliensis
induces invasion of mast cell precursors from
peripheral blood to small intestine. Blood, in
press.
3 Nivva Y, Kasugai T, Ohno K, Morimoto M, Yamazaki M, Dohmac K, Nishimune Y, Kondo K.
Kitamura Y: Anemia and mast cell depletion in
mutant rats that arc homozygous at ‘white spot­
ting' ( Mi) locus. Blood 19 9 1;78:1936-1941.
4 Tsujimura T, Hirota S, Nomura S, Niwa Y. Yamazaki M.TonoT, Morii E, Kim MM, Kondo K,
Nishimune Y, Kitamura Y: Characterization of
Mi mutant allele of rats; A 12 base deletion in
tyrisonc kinase domain o f c-kil gene. Blood
1991;78:1942-1946.
5 Kasugai T, Okada M, Morimoto M, Arizono N,
Maeyama K, Yamada M, Tei H. Dohmae K,
Onouc H, Newlands GFJ, Watanabe T, Nishi­
mune Y. Miller MRP, Kitamura Y: Infection of
Nipposlrongylus brasiliensis induces normal
increase of basophils in mast-cell deficient Mi/
Mi rats with a small deletion at the kinase do­
main o f c-A/7. Blood 1993;81:2521-2529.
56
6 Arizono N, Kasugai T, Yamada M, Okada M.
Morimoto M. Tei H, Newlands GEJ, Miller
HRP, Kitamura Y: Infection o f Nipposlrongylus
brasiliensis induces development of mucosaltype but not connective tissue-type mast cells in
genetically mast-cell deficient MS/Mi rats,
iilood 1993:81:2572-2579.
7 Tono T, Tsujimura T, Koshimizu U, Kasugai T.
Adachi S. Isozaki K, Nishikawa SI, Morimoto
M, Nishimune Y, Nomura S, Kitamura Y: Defi­
cient transcription o f c-kit gene in cultured mast
cells of
mice that have nearly normal
number o f erythrocytes and normal c-kit coding
region. Blood 1992;80:1448-1453.
8 Yamazaki M. Tsujimura T. Isozaki K. Onoue H.
Nomura S, Kitamura Y: c-kit gene is expressed
by skin mast cells in embryos but not in puppies
o f \V''/W'h mice: Age-dependent abolishment
o f c-kil gene expression. Blood 1994:83:3509—
3516.
9 Furitsu T. Tsujimura T, Tono T, Ikeda 11. Kitayama H. Koshimizu U, Sugahara H, Butterfield
JH, Ashman LK. Kanayama Y, Matsuzawa Y,
Kitamura Y, Kanakura Y: Identification o f mu­
tations in the coding region of the proto-oncogcnc c-kil in a human mast cell leukemia cell
line causing ligand-independent activation of ckil product. J Clin Invest 1993:92:1736-1744.
10 Tsujimura T, Furitsu T, Morimoto M, Isozaki K,
Nomura S, Matsuzawa Y, Kitamura Y. Kanak­
ura Y: Ligand-independent activation of c-kil
receptor tyrosine kinase in a murine mastocyto­
ma cell line P-815 generated by a point muta­
tion. Blood 1994:83:2619-2626.
11 Kitayama H, Kanakura Y. Furitsu T. Tsujimura
T, Oritani K, Ikeda H, Mitsui H, Kanayama Y.
Kitamura Y. Matsuzawa Y: C'onstitutively acti­
vating mutations of c-kil receptor tyrosine ki­
nase confer factor-independent growth and tumorigcnicity of factor-dependent hematopoiet­
ic cell lines. Blood 1995:85:790-798.
Kitamura/Tsujimura/Jippo/Kasugai/
Kanakura
M ast C ells and c-kit
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References
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