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Expression of p210bcr/abl by metallothionein promoter induced T-cell
leukemia in transgenic mice
H Honda, T Fujii, M Takatoku, H Mano, ON Witte, Y Yazaki and H Hirai
Department of Molecular Biology, Jichi Medical School, Tochigi-ken, Japan.
The p210bcr/abl chimeric protein is considered to be implicated in the
pathogenesis of Philadelphia chromosome-positive human leukemias. To
investigate its biologic function in vivo, we generated transgenic mice
expressing p210bcr/abl driven by the metallothionein enhancer/promoter. Two
of six founder mice and the transgenic progeny developed leukemias several
months after birth. In the leukemic tissues, the expression of the
p210bcr/abl transgene product was detected and the increased
tyrosine-phosphorylation of cellular proteins was observed. The expressed
p210bcr/abl transgene product was shown to possess an enhanced kinase
activity. The leukemic cells showed rearrangements in the T-cell receptor
loci, indicating that the leukemic cells were monoclonal and committed to
the T-cell lineage. Polymerase chain reaction analysis for tissue
distribution of p210bcr/abl expression showed that, in the transgenic line
that reproducibly developed leukemias, p210bcr/abl was expressed in the
hematopoietic tissues such as thymus and spleen; on the other hand, in the
transgenic lines that have not developed leukemias, p210bcr/abl expression
was detected only in the nonhematopoietic tissues such as the brain and
kidney. These results suggest that the tumorigenicity of the p210bcr/abl
chimeric protein is restricted to the hematopoietic tissues in vivo and
that an event enhancing p210bcr/abl expression contributed a proliferative
advantage to hematopoietic precursor cells and eventually developed T- cell
leukemia in transgenic mice.
Volume 85,
Issue 10,
pp. 2853-2861,
05/15/1995
Copyright © 1995 by The American Society of Hematology
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