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Inducible chronic phase of myeloid leukemia with expansion of hematopoietic stem cells in a transgenic model of BCR-ABL leukemogenesis.
Blood 2005; 105(1):324-34Blood

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.

Authors+Show Affiliations

Department of Hematology/Oncology, Harvard Institutes of Medicine, Harvard Medical School, Boston, MA 02115, USA.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15331442

Citation

Koschmieder, Steffen, et al. "Inducible Chronic Phase of Myeloid Leukemia With Expansion of Hematopoietic Stem Cells in a Transgenic Model of BCR-ABL Leukemogenesis." Blood, vol. 105, no. 1, 2005, pp. 324-34.
Koschmieder S, Göttgens B, Zhang P, et al. Inducible chronic phase of myeloid leukemia with expansion of hematopoietic stem cells in a transgenic model of BCR-ABL leukemogenesis. Blood. 2005;105(1):324-34.
Koschmieder, S., Göttgens, B., Zhang, P., Iwasaki-Arai, J., Akashi, K., Kutok, J. L., ... Huettner, C. S. (2005). Inducible chronic phase of myeloid leukemia with expansion of hematopoietic stem cells in a transgenic model of BCR-ABL leukemogenesis. Blood, 105(1), pp. 324-34.
Koschmieder S, et al. Inducible Chronic Phase of Myeloid Leukemia With Expansion of Hematopoietic Stem Cells in a Transgenic Model of BCR-ABL Leukemogenesis. Blood. 2005 Jan 1;105(1):324-34. PubMed PMID: 15331442.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inducible chronic phase of myeloid leukemia with expansion of hematopoietic stem cells in a transgenic model of BCR-ABL leukemogenesis. AU - Koschmieder,Steffen, AU - Göttgens,Berthold, AU - Zhang,Pu, AU - Iwasaki-Arai,Junko, AU - Akashi,Koichi, AU - Kutok,Jeffery L, AU - Dayaram,Tajhal, AU - Geary,Kristin, AU - Green,Anthony R, AU - Tenen,Daniel G, AU - Huettner,Claudia S, Y1 - 2004/08/26/ PY - 2004/8/28/pubmed PY - 2005/2/11/medline PY - 2004/8/28/entrez SP - 324 EP - 34 JF - Blood JO - Blood VL - 105 IS - 1 N2 - 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. SN - 0006-4971 UR - https://www.unboundmedicine.com/medline/citation/15331442/Inducible_chronic_phase_of_myeloid_leukemia_with_expansion_of_hematopoietic_stem_cells_in_a_transgenic_model_of_BCR_ABL_leukemogenesis_ L2 - http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=15331442 DB - PRIME DP - Unbound Medicine ER -