Tomasson M H, Williams I R, Hasserjian R, Udomsakdi C, McGrath S M, Schwaller J, Druker B, Gilliland D G
Division of Hematology, Brigham and Women's Hospital, Boston, MA, USA.
Blood. 1999 Mar 1;93(5):1707-14.
The TEL/PDGFbetaR fusion protein is expressed as the consequence of a recurring t(5;12) translocation associated with chronic myelomonocytic leukemia (CMML). Unlike other activated protein tyrosine kinases associated with hematopoietic malignancies, TEL/PDGFbetaR is invariably associated with a myeloid leukemia phenotype in humans. To test the transforming properties of TEL/PDGFbetaR in vivo, and to analyze the basis for myeloid lineage specificity in humans, we constructed transgenic mice with TEL/PDGFbetaR expression driven by a lymphoid-specific immunoglobulin enhancer-promoter cassette. These mice developed lymphoblastic lymphomas of both T and B lineage, demonstrating that TEL/PDGFbetaR is a transforming protein in vivo, and that the transforming ability of this fusion is not inherently restricted to the myeloid lineage. Treatment of TEL/PDGFbetaR transgenic animals with a protein tyrosine kinase inhibitor with in vitro activity against PDGFbetaR (CGP57148) resulted in suppression of disease and a prolongation of survival. A therapeutic benefit was apparent both in animals treated before the development of overt clonal disease and in animals transplanted with clonal tumor cells. These results suggest that small-molecule tyrosine kinase inhibitors may be effective treatment for activated tyrosine kinase-mediated malignancies both early in the course of disease and after the development of additional transforming mutations.
TEL/PDGFβR融合蛋白是由与慢性粒单核细胞白血病（CMML）相关的复发性t(5;12)易位产生的。与其他与造血系统恶性肿瘤相关的活化蛋白酪氨酸激酶不同，TEL/PDGFβR在人类中总是与髓系白血病表型相关。为了测试TEL/PDGFβR在体内的转化特性，并分析人类髓系谱系特异性的基础，我们构建了由淋巴特异性免疫球蛋白增强子-启动子盒驱动TEL/PDGFβR表达的转基因小鼠。这些小鼠发生了T和B谱系的淋巴细胞淋巴瘤，表明TEL/PDGFβR在体内是一种转化蛋白，并且这种融合蛋白的转化能力并非固有地局限于髓系谱系。用对PDGFβR具有体外活性的蛋白酪氨酸激酶抑制剂（CGP57148）治疗TEL/PDGFβR转基因动物，导致疾病抑制和生存期延长。在明显的克隆性疾病发展之前接受治疗的动物以及移植了克隆性肿瘤细胞的动物中，治疗益处都很明显。这些结果表明，小分子酪氨酸激酶抑制剂可能对疾病早期以及在发生其他转化突变后由活化酪氨酸激酶介导的恶性肿瘤是有效的治疗方法。
