The expression of ETV6/CBFA2 (TEL/AML1) is not sufficient for the transformation of hematopoietic cell lines in vitro or the induction of hematologic disease in vivo
The expression of ETV6/CBFA2 (TEL/AML1) is not sufficient for the transformation of hematopoietic cell lines in vitro or the induction of hematologic disease in vivo
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DOI：
10.1016/s0165-4608(01)00518-0
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发表时间：
2001-10-15
影响因子：
--
通讯作者：
Gilliland, DG
中科院分区：
文献类型：
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作者：
Andreasson, P;Schwaller, J;Gilliland, DG
ETV 6/CBFA 2（TEL/AML 1）是儿童急性淋巴细胞白血病最常见的遗传异常，与良好的预后相关。为了研究ETV 6/CBFA 2对细胞转化的影响，将融合基因克隆到鼠嗜亲性逆转录病毒载体中，并转导到IL-3依赖性Ba/F3和32Dcl.3和IL-7依赖性IxN/2b鼠造血细胞系中。ETV 6/CBFA 2的不同变体（对应于CBFA 2可变剪接变体）和相互产物CBFA 2/ETV 6在这些细胞系中的每一个中稳定表达。然而，尽管蛋白质印迹分析证明了每种变体的表达，但表达CBFA 2/ETV 6或变体的稳定细胞系均不赋予因子非依赖性生长。我们通过产生转基因小鼠进一步研究了ETV 6/CBFA 2在体内表达的作用，在转基因小鼠中，使用免疫球蛋白重链增强子/启动子将融合体的表达导向淋巴细胞。四个创始人小鼠进行了鉴定，显示嵌合产物的传输和表达。这些小鼠被繁殖了五代，并被跟踪了超过24个月。小鼠没有发展成恶性血液病，也没有显示组织病理学、形态学或免疫表型异常，尽管在每个系中证实了ETV 6/CBFA 2表达。我们得出结论，ETV 6/CBFA 2单独表达不足以诱导造血细胞系中的生长因子依赖性或转基因小鼠中的血液病。(C)2001 Elsevier Science Inc. All rights reserved.
ETV6/CBFA2 (TEL/AML1) is the most frequent genetic abnormality associated with acute lymphoblastic leukemias in children, and is associated with a favorable prognosis. To investigate the influence of ETV6/CBFA2 on cellular transformation, the fusion gene was cloned into a murine ecotropic retroviral vector and transduced into IL-3-dependent Ba/F3 and 32Dcl.3 and IL-7-dependent IxN/2b murine hematopoietic cell lines. Different variants of ETV6/CBFA2, corresponding to CBFA2 alternatively spliced variants, and the reciprocal product CBFA2/ETV6, were stably expressed in each of these cell lines. However, although Western blot analysis demonstrated expression of each variant, none of the stable cell lines expressing CBFA2/ETV6 or the variants conferred factor-independent growth. We further investigated the effect of ETV6/CBFA2 expression in vivo by generating transgenic mice in which expression of the fusion was directed to lymphoid cells using the immunoglobulin heavy chain enhancer/promoter. Four founder mice were identified showing transmission and expression of the chimeric product. The mice were bred for five generations and followed for more than 24 months. The mice did not develop a malignant hematologic disorder, nor did they display histopatholagic, morphologic, or immunophenatypic abnormalities, although ETV6/CBFA2 expression was confirmed in each line. We conclude that the expression of ETV6/ CBFA2 alone is not sufficient for induction of growth factor independence in hematopoietic cell lines or hematologic disease in transgenic mice. (C) 2001 Elsevier Science Inc. All rights reserved.