Inducible chronic phase of myeloid leukemia with expansion of hematopoietic stem cells in a transgenic model of BCR-ABL leukemogenesis.
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.
Department of Hematology/Oncology, Harvard Institutes of Medicine, Harvard Medical School, Boston, MA 02115, USA.
Steffen
S
Koschmieder
Berthold
B
Göttgens
Pu
P
Zhang
Junko
J
Iwasaki-Arai
Koichi
K
Akashi
Jeffery L
JL
Kutok
Tajhal
T
Dayaram
Kristin
K
Geary
Anthony R
AR
Green
Daniel G
DG
Tenen
Claudia S
CS
Huettner
D000818:Animals; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D016044:Fusion Proteins, bcr-abl / Q000235:genetics* / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000473:pathology* / Q000628:therapy; D007964:Leukocytosis / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology; D009361:Neoplasm Invasiveness; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D013154:Spleen / Q000378:metabolism / Q000473:pathology; D033581:Stem Cell Transplantation; D015996:Survival Rate; D015533:Transcriptional Activation / Q000235:genetics
D016044:Fusion Proteins, bcr-abl