Expression of p210bcr/abl by metallothionein promoter induced T-cell leukemia in transgenic mice.
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.
Honda
H
H
Department of Molecular Biology, Jichi Medical School, Tochigi-ken, Japan.
Fujii
T
T
Takatoku
M
M
Mano
H
H
Witte
O N
ON
Yazaki
Y
Y
Hirai
H
H
D000818:Animals; D001483:Base Sequence; D002999:Clone Cells; D017931:DNA Primers / Q000737:chemistry; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor / Q000235:genetics; D015334:Gene Rearrangement, gamma-Chain T-Cell Antigen Receptor; D016313:Genes, abl; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics*; D015458:Leukemia, T-Cell / Q000235:genetics*; D008297:Male; D008668:Metallothionein / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010375:Pedigree; D019000:Phosphotyrosine; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics; D014018:Tissue Distribution; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D017931:DNA Primers; D012333:RNA, Messenger; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta; D019000:Phosphotyrosine; D014443:Tyrosine; D008668:Metallothionein; D016044:Fusion Proteins, bcr-abl