Model mice for BCR/ABL-positive leukemias.
p210bcr/abl is detected in almost all chronic myelogenous leukemia (CML) patients and a significant number of acute lymphoblastic leukemia (ALL) cases. It is generated by a reciprocal chromosomal translocation, t(9;22) (q34;q11), and the enhanced kinase activity of the protein is believed to be implicated in the pathogenesis of the diseases. To examine its oncogenicity in vivo and to create an animal model for BCR/ABL-positive leukemias, we generated transgenic mice expressing p210bcr/abl driven by the promoter of the mouse tec gene, a cytoplasmic tyrosine kinase preferentially expressed in early hematopoietic progenitors. While the founder mice showed excessive proliferation of lymphoblasts shortly after birth and were diagnosed as ALL, the transgenic progeny reproducibly exhibited marked granulocyte hyperplasia with thrombocytosis after a long latent period, which closely resembles the clinical course of human CML. In addition, to investigate whether loss of p53 would play a role in the transition from chronic phase to blast crisis of CML, we crossmated p210bcr/abl transgenic (BCR/ABLtg/-) mice with p53 heterozygous (p53+/-) mice and generated p210bcr/abl transgenic, p53 heterozygous (BCR/ABLtg/- p53+/-) mice, in which a somatic alteration in the residual p53 allele directly abrogates p53 function. The BCR/ABLtg/- p53+/- mice exhibited rapid proliferation of blast cells and died in a short period compared with their wild-type (BCR/ABL-/- p53+/+), p53 heterozygous (BCR/ABL-/- p53+/-), and p210bcr/abl transgenic (BCR/ABLtg/- p53+/+) littermates. Interestingly, the normal p53 allele was frequently and preferentially lost in the tumor tissues, providing in vivo evidence that acquired loss of p53 contributes to the blastic transformation of p210bcr/abl-expressing hematopoietic cells. Our transgenic mice will be a useful model for investigating oncogenic properties of p210bcr/abl in vivo and will provide insights into the molecular mechanism(s) underlying the progression from chronic phase to blast crisis of CML.
Honda
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Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
Hirai
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D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D005838:Genotype; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000209:etiology / Q000235:genetics / Q000473:pathology; D011401:Promoter Regions, Genetic; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D016159:Tumor Suppressor Protein p53; D016044:Fusion Proteins, bcr-abl