Kanie T, Abe A, Matsuda T, Kuno Y, Towatari M, Yamamoto T, Saito H, Emi N, Naoe T
Department of Hematology, Graduate School of Medicine, Nagoya University, Nagoya, Japan.
Leukemia. 2004 Mar;18(3):548-55. doi: 10.1038/sj.leu.2403266.
We previously reported the fusion of the TEL gene to the Syk gene in myelodysplastic syndrome with t(9;12)(q22;p12). TEL-Syk fusion transformed interleukin-3 (IL-3)-dependent murine hematopoietic cell line BaF3 to growth factor independence. Here, we investigate the intracellular signal transduction of the stable transfectants. TEL-Syk fusion protein was associated with the p85 subunit of phosphatidyl inositol 3 kinase (PI3-K) followed by the activation of Akt in the absence of IL-3. Vav, phospholipase C-gamma2 and mitogen-activated protein kinase (MAPK) were also constitutively activated. TEL-Syk also activated the signal transducer and activator of transcription 5 (STAT5) in the absence of Janus kinase 2 activation. None of these kinases were phosphorylated in the BaF3 cells transfected with TELDeltaPNT-Syk in which the oligomerization domain of TEL was deleted. Inhibitor analysis showed that the MAPK pathway was important in TEL-Syk-mediated cell proliferation. The immunofluorescence technique revealed that the TEL-Syk fusion protein was located in the cytoplasm. These data suggest that TEL-Syk fusion protein in the cytoplasm leads to the constitutive activation of PI3-K/Akt, MAPK and STAT5 signal pathways, which are closely involved in IL-3-independent cell proliferation of BaF3 cells.
我们之前报道过，在伴有t(9;12)(q22;p12)的骨髓增生异常综合征中，TEL基因与Syk基因发生了融合。TEL-Syk融合基因将依赖白细胞介素-3（IL-3）的小鼠造血细胞系BaF3转化为不依赖生长因子的细胞系。在此，我们研究稳定转染子的细胞内信号转导。在没有IL-3的情况下，TEL-Syk融合蛋白与磷脂酰肌醇3激酶（PI3-K）的p85亚基相关联，随后Akt被激活。Vav、磷脂酶C-γ2和丝裂原活化蛋白激酶（MAPK）也持续被激活。在没有Janus激酶2激活的情况下，TEL-Syk也激活了信号转导及转录激活因子5（STAT5）。在用缺失TEL寡聚化结构域的TELDeltaPNT-Syk转染的BaF3细胞中，这些激酶均未发生磷酸化。抑制剂分析表明，MAPK途径在TEL-Syk介导的细胞增殖中起重要作用。免疫荧光技术显示，TEL-Syk融合蛋白位于细胞质中。这些数据表明，细胞质中的TEL-Syk融合蛋白导致PI3-K/Akt、MAPK和STAT5信号通路的持续激活，这些通路与BaF3细胞不依赖IL-3的细胞增殖密切相关。
