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Development of Acute Lymphoblastic Leukemia and Myeloproliferative
Disorder in Transgenic Mice Expressing p210bcr/abl:
A Novel Transgenic Model for Human Ph1-Positive
Leukemias
Hiroaki Honda,
Hideaki Oda,
Takahiro Suzuki,
Tsuyoshi Takahashi,
Owen N. Witte,
Keiya Ozawa,
Takatoshi Ishikawa,
Yoshio Yazaki, and
Hisamaru Hirai
From the Third Department of Internal Medicine, Faculty of Medicine,
and the Department of Pathology, University of Tokyo, Tokyo, Japan; the
Department of Microbiology and Molecular Genetics, Howard Huges Medical
Institute, University of California; and the Department of Molecular
Biology, Jichi Medical School, Japan.
The Philadelphia (Ph) chromosome can be detected in
chronic myelogenous leukemia (CML) and a significant number of acute lymphoblastic leukemia (ALL) cases. Generation of
p210bcr/abl, a chimeric protein with enhanced
kinase activity, is thought to be involved in the pathogenesis of these
diseases. To elucidate the biological properties of
p210bcr/abl and to create an animal model for human
Ph1-positive leukemias, we generated transgenic mice
expressing p210bcr/abl driven by the
promoter of the tec gene, a cytoplasmic tyrosine-kinase preferentially expressed in the hematopoietic lineage. The founder mice
showed excessive proliferation of lymphoblasts shortly after birth and
were diagnosed as suffering from ALL based on surface marker and
Southern blot analyses. Expression and enhanced kinase activity of the
p210bcr/abl transgene product were detected in the
leukemic tissues. In contrast, transgenic progeny exhibited marked
granulocyte hyperplasia with thrombocytosis after a long latent period
and developed myeloproliferative disorders (MPDs) closely resembling
human CML. Expression of p210bcr/abl mRNA
in the proliferating granulocytes was detected by RT-PCR. In
particular, one MPD mouse showed remarkable proliferation of blast
cells in the lung, which might represent an extramedullar blast crisis.
The results demonstrate that the expression of
p210bcr/abl in hematopoietic progenitor cells in
transgenic mice can contribute to two clinically distinct hematopoietic
malignancies, CML and ALL, indicating that this transgenic system
provides a novel transgenic model for human Ph1-positive
leukemias.
Blood, Vol. 91 No. 6 (March 15), 1998:
pp. 2067-2075
© 1998 by The American Society of Hematology.
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