Cited by 188

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Inducible chronic phase of myeloid leukemia with expansion of hematopoietic stem cells in a transgenic model of BCR-ABL leukemogenesis

Koschmieder, Steffen, Göttgens, Berthold, Zhang, Pu, Iwasaki-Arai, Junko, Akashi, Koichi, Kutok, Jeffery L., Dayaram, Tajhal, Geary, Kristin, Green, Anthony R., Tenen, Daniel G., Huettner, Claudia S.·2005·Blood

Abstract

To develop murine models of leukemogenesis, a series of transgenic mice expressing BCR-ABL in different hematopoietic cell subsets was generated. Here we describe targeted expression of P210 BCR-ABL in stem and progenitor cells of murine bone marrow using the tet-off system. The transactivator protein tTA was placed under the control of the murine stem cell leukemia (SCL) gene 3′ enhancer. Induction of BCR-ABL resulted in neutrophilia and leukocytosis, and the mice became moribund within 29 to 122 days. Autopsy of sick mice demonstrated splenomegaly, myeloid bone marrow hyperplasia, and extramedullary myeloid cell infiltration of multiple organs. BCR-ABL mRNA and protein were detectable in the affected organs. Fluorescence-activated cell sorter (FACS) analysis demonstrated a significant increase in mature and immature myeloid cells in bone marrow and spleen, together with increased bilineal B220+/Mac-1+ cells in the bone marrow. tTA mRNA was expressed in FACS-sorted hematopoietic stem cells expanded 26-fold after BCR-ABL induction. Thirty-one percent of the animals demonstrated a biphasic phenotype, consisting of neutrophilia and subsequent B-cell lymphoblastic disease, reminiscent of blast crisis. In summary, this mouse model recapitulates many characteristics of human chronic myeloid leukemia (CML) and may help elucidate basic leukemogenic mechanisms in CML stem cells during disease initiation and progression. (Blood. 2005;105:324-334)

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Crossref · 10.1182/blood-2003-12-4369

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Cited by

Metadata

Authors
Koschmieder, S., Göttgens, B., Zhang, P., Iwasaki-Arai, J., Akashi, K., Kutok, J. L., Dayaram, T., Geary, K., Green, A. R., Tenen, D. G., & Huettner, C. S.
Affiliations
From the Department of Hematology/Oncology, Harvard Institutes of Medicine, Harvard Medical School, Boston, MA; Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, United Kingdom; Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; Department of Pathology, Brigham and Women's Hospital, Boston, MA; and Blood Center of South Eastern Wisconsin, Milwaukee.
Venue
Blood
Published
2005-01-01
Volume
105
Issue
1
Pages
324-334
ISSN
  • 0006-4971
  • 1528-0020
Cited by
188
References
6
Language
en

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