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Blood, 15 April 2003, Vol. 101, No. 8, pp. 2990-2995
HEMATOPOIESIS
Impaired neutrophil maturation in truncated murine G-CSF
receptor-transgenic mice
Tetsuo Mitsui,
Sumiko Watanabe,
Yoshihiro Taniguchi,
Sachiyo Hanada,
Yasuhiro Ebihara,
Takeshi Sato,
Toshio Heike,
Masao Mitsuyama,
Tatsutoshi Nakahata, and
Kohichiro Tsuji
From the Division of Cellular Therapy, The Advanced
Clinical Research Center, and Department of Molecular and Development
Biology, The Institute of Medical Science, The University of Tokyo,
Tokyo, Japan; and Departments of Pediatrics and
Microbiology, Graduate School of Medicine, Kyoto University, Kyoto,
Japan.
Severe congenital neutropenia (SCN) is a hematopoietic disorder
characterized by neutropenia in peripheral blood and maturation arrest
of neutrophil precursors in bone marrow. Patients with SCN may evolve
to have myelodysplastic syndrome or acute myelocytic leukemia. In
approximately 20% of SCN cases, a truncation mutation is found in the
cytoplasmic region of the granulocyte colony-stimulating factor
receptor (G-CSFR). We then generated mice carrying murine wild-type
G-CSFR and its mutants equivalent to truncations at amino acids 718 and
731 in human G-CSFR, those were reported to be related to leukemic
transformation of SCN. Although numbers of peripheral white blood
cells, red blood cells, and platelets did not differ among mutant and
wild-type G-CSFR transgenic (Tg) mice, both of the mutant receptor Tg
mice had one third of peripheral neutrophil cell counts compared with
wild-type receptor Tg mice. The mutant receptor Tg mice also showed
impaired resistance to the infection with Staphylococcus
aureus. Moreover, bone marrow of these Tg mice had an increased
percentage of immature myeloid cells, a feature of SCN. This maturation
arrest was also observed in in vitro cultures of bone marrow cells of
truncated G-CSFR Tg mice under G-CSF stimulation. In addition, clonal
culture of bone marrow cells of the truncated G-CSFR Tg mice showed the
hypersensitivity to G-CSF in myeloid progenitors. Our Tg mice may be
useful in the analysis of the role of truncated G-CSFR in SCN pathobiology.
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