Transforming properties of chimeric TEL-JAK proteins in Ba/F3 cells
Transforming properties of chimeric TEL-JAK proteins in Ba/F3 cells
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DOI：
10.1182/blood.v95.6.2076
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发表时间：
2000-03-15
期刊：
影响因子：
20.3
通讯作者：
Bernard, OA
中科院分区：
文献类型：
--
作者：
Lacronique, V;Boureux, A;Bernard, OA
细胞因子信号通路在肿瘤发生中的参与早已被假定。最近，在人类白血病中已经报道了编码酪氨酸Janus激酶2（JAK 2）的基因的重排，表明直接的JAK信号转导和转录激活因子（STAT）介导的白血病过程。白血病相关的TEL-JAK 2融合蛋白由易位的ets白血病（TEL）蛋白的寡聚化结构域融合到JAK 2的催化结构域形成，TEL介导的寡聚化导致组成型酪氨酸激酶活性，其进而能够赋予鼠造血白细胞介素-3（IL-3）依赖性Ba/F3细胞系生长因子独立性。本研究的结果表明，含有TEL的寡聚化结构域和Jak 1、Jak 2、JAK 3或TYK 2的酪氨酸激酶结构域的融合蛋白具有相似的性质，并且能够有效地替代由IL-3控制的存活和促有丝分裂信号，而不伴随IL-3受体的激活，电泳迁移率变动分析表明Stat 5是表达TEL-Jak 2和TEL-Jak 1的细胞中唯一活化的Stats因子，而其他Stats，即Stat 1和Stat 3，可以在TEL-JAK 3-，TEL-TYK 2-，并且也在表达TEL-ABL的Ba/F3细胞中。在所有非依赖于嘌呤的细胞系中观察到Stat 5靶基因pim-1、osm和Cis的高水平表达。此外，Stat 5A的显性负性形式的表达显著干扰Ba/F3细胞中由TEL-Jak 2介导的生长因子独立性过程。因为BCR-ABL和TEL-PDGF β R癌蛋白也激活Stat 5，所以该因子的激活应该是激活酪氨酸激酶介导的白血病发生的关键步骤。(C)2000年，美国血液学会。
The involvement of the cytokine signaling pathway in oncogenesis has long been postulated. Recently, rearrangements of the gene encoding the tyrosine janus kinase 2 (JAK2) have been reported in human leukemias indicating a direct JAK-signal transduction and activator of transcription (STAT)-mediated leukemic process. The leukemia-associated TEL-JAK2 fusion protein is formed by the oligomerization domain of the translocated ets leukemia (TEL) protein fused to the Catalytic domain of JAK2, TEL-mediated oligomerization results in a constitutive tyrosine kinase activity that, in turn, is able to confer growth factor independence to the murine hematopoietic interleukin-3 (IL-3)-dependent Ba/F3 cell line. Results of the present study indicate that fusion proteins containing the oligomerization domain of TEL and the tyrosine kinase domains of Jak1, Jak2, JAK3, or TYK2 share similar properties and are able to efficiently substitute for the survival and mitogenic signals controlled by IL-3, without concomitant activation of the IL-3 receptor, Electrophoretic mobility shift assays demonstrated Stat5 as the only activated Stat factor in TEL-Jak2- and TEL-Jak1-expressing cells, whereas other Stats, namely Stat1 and Stat3, could be detected in TEL-JAK3-, TEL-TYK2-, and also in TEL-ABL-expressing Ba/F3 cells. High levels of expression of the Stat5-target genes pim-l, osm, and Cis were observed In all the cytokine-independent cell lines. Furthermore, the expression of a dominant negative form of Stat5A markedly interfered with the growth factor independence process mediated by TEL-Jak2 in Ba/F3 cells. Because the BCR-ABL and TEL-PDGF beta R oncoproteins also activate Stat5, activation of this factor should be a crucial step in activated tyrosine kinase-mediated leukemogenesis. (C) 2000 by The American Society of Hematology.