Honda H, Oda H, Suzuki T, Takahashi T, Witte O N, Ozawa K, Ishikawa T, Yazaki Y, Hirai H
Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan.
Blood. 1998 Mar 15;91(6):2067-75.
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 p210(bcr/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.
费城（Ph）染色体可在慢性粒细胞白血病（CML）以及相当数量的急性淋巴细胞白血病（ALL）病例中检测到。p210bcr/abl是一种具有增强激酶活性的嵌合蛋白，其生成被认为与这些疾病的发病机制有关。为了阐明p210bcr/abl的生物学特性并建立人类Ph1阳性白血病的动物模型，我们构建了转基因小鼠，这些小鼠由tec基因的启动子驱动表达p210bcr/abl，tec基因是一种优先在造血谱系中表达的细胞质酪氨酸激酶。初代小鼠在出生后不久就出现了淋巴母细胞过度增殖的情况，基于表面标志物和Southern印迹分析被诊断为患有ALL。在白血病组织中检测到了p210bcr/abl转基因产物的表达和增强的激酶活性。相比之下，转基因后代在长时间潜伏期后表现出明显的粒细胞增生并伴有血小板增多症，并且发展出了与人类CML极为相似的骨髓增殖性疾病（MPD）。通过RT-PCR检测到增殖的粒细胞中p210(bcr/abl) mRNA的表达。特别是，一只患有MPD的小鼠肺部出现了明显的原始细胞增殖，这可能代表髓外原始细胞危象。结果表明，转基因小鼠造血祖细胞中p210bcr/abl的表达可导致两种临床特征不同的造血系统恶性肿瘤，即CML和ALL，这表明该转基因系统为人类Ph1阳性白血病提供了一种新的转基因模型。
