Development of acute lymphoblastic leukemia and myeloproliferative disorder in transgenic mice expressing p210bcr/abl:: A novel transgenic model for human Ph1-positive leukemias
Development of acute lymphoblastic leukemia and myeloproliferative disorder in transgenic mice expressing p210bcr/abl:: A novel transgenic model for human Ph1-positive leukemias
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DOI：
10.1182/blood.v91.6.2067.2067_2067_2075
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发表时间：
1998-03-15
期刊：
影响因子：
20.3
通讯作者：
Hirai, H
中科院分区：
文献类型：
--
作者：
Honda, H;Oda, H;Hirai, H
费城 (Ph-1) 染色体可在慢性粒细胞白血病 (CML) 和大量急性淋巴细胞白血病 (ALL) 病例中检测到。 p210(bcr/abl)是一种激酶活性增强的嵌合蛋白，被认为与这些疾病的发病机制有关。为了阐明p210(bcr/abl)的生物学特性并创建人类Ph-1阳性白血病的动物模型，我们培育了由tec基因B细胞质酪氨酸激酶启动子驱动的表达p210(bcr/abl)的转基因小鼠优先在造血谱系中表达。创始人小鼠在出生后不久就表现出淋巴母细胞过度增殖，并根据表面标记和 Southern blot 分析被诊断为患有 ALL。在白血病组织中检测到p210(bcr/abl)转基因产物的表达末端增强的激酶活性。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和血小板增多，并发展出与人类 CML 非常相似的骨髓增殖性疾病 (MPD)。 RT-PCR检测增殖粒细胞中p210(bcr/abl)mRNA的表达。特别是，一只 MPD 小鼠在肺部显示出原始细胞的显着增殖，这可能代表髓外原始细胞危机。结果表明，转基因小鼠造血祖细胞中p210（bcr/abl）的表达可导致两种临床上不同的造血系统恶性肿瘤：CML和ALL，表明该转基因系统为人类Ph-1阳性白血病提供了一种新的转基因模型。 (C) 1998 年，美国血液学会。
The Philadelphia (Ph-1) chromosome can be detected in chronic myelogenous leukemia (CML) and a significant number of acute lymphoblastic leukemia (ALL) cases. Generation of p210(bcr/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 p210(bcr/abl) and to create an animal model for human Ph-1-positive leukemias, we generated transgenic mice expressing p210(bcr/abl) driven by the promoter of the tec gene, B 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 end enhanced kinase activity of the p210(bcr/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 p210(bcr/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 Ph-1-positive leukemias. (C) 1998 by The American Society of Hematology.