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Blood, 1 January 2005, Vol. 105, No. 1, pp. 324-334. Prepublished online as a Blood First Edition Paper on August 26, 2004; DOI 10.1182/blood-2003-12-4369. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-12-4369v1 105/1/324    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Koschmieder, S. Articles by Huettner, C. S. Search for Related Content PubMed PubMed Citation Articles by Koschmieder, S. Articles by Huettner, C. S. Related Collections Hematopoiesis and Stem Cells Neoplasia Oncogenes and Tumor Suppressors Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Inducible chronic phase of myeloid leukemia with expansion of hematopoietic stem cells in a transgenic model of BCR-ABL leukemogenesis Steffen Koschmieder, Berthold Göttgens, Pu Zhang, Junko Iwasaki-Arai, Koichi Akashi, Jeffery L. Kutok, Tajhal Dayaram, Kristin Geary, Anthony R. Green, Daniel G. Tenen, and Claudia S. Huettner 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. 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. 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