Honda H, Fujii T, Takatoku M, Mano H, Witte O N, Yazaki Y, Hirai H
Department of Molecular Biology, Jichi Medical School, Tochigi-ken, Japan.
Blood. 1995 May 15;85(10):2853-61.
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.
p210bcr/abl嵌合蛋白被认为与费城染色体阳性的人类白血病发病机制有关。为了研究其在体内的生物学功能，我们构建了由金属硫蛋白增强子/启动子驱动表达p210bcr/abl的转基因小鼠。6只奠基小鼠中有2只及其转基因后代在出生后几个月发生了白血病。在白血病组织中，检测到了p210bcr/abl转基因产物的表达，并观察到细胞蛋白酪氨酸磷酸化增加。所表达的p210bcr/abl转基因产物显示具有增强的激酶活性。白血病细胞在T细胞受体基因座发生重排，表明白血病细胞是单克隆的且定向于T细胞谱系。对p210bcr/abl表达的组织分布进行聚合酶链反应分析表明，在可重复性发生白血病的转基因系中，p210bcr/abl在胸腺和脾脏等造血组织中表达；另一方面，在未发生白血病的转基因系中，仅在脑和肾等非造血组织中检测到p210bcr/abl表达。这些结果表明，p210bcr/abl嵌合蛋白的致瘤性在体内仅限于造血组织，并且增强p210bcr/abl表达的事件赋予造血前体细胞增殖优势，并最终在转基因小鼠中发生T细胞白血病。
