Guasch G, Ollendorff V, Borg J P, Birnbaum D, Pébusque M J
Laboratoire d'Oncologie Moléculaire, INSERM U 119, IFR 57, Marseille, France.
Mol Cell Biol. 2001 Dec;21(23):8129-42. doi: 10.1128/MCB.21.23.8129-8142.2001.
The FOP-fibroblast growth factor receptor 1 (FGFR1) fusion protein is expressed as a consequence of a t(6;8) (q27;p12) translocation associated with a stem cell myeloproliferative disorder with lymphoma, myeloid hyperplasia and eosinophilia. In the present report, we show that the fusion of the leucine-rich N-terminal region of FOP to the catalytic domain of FGFR1 results in conversion of murine hematopoietic cell line Ba/F3 to factor-independent cell survival via an antiapoptotic effect. This survival effect is dependent upon the constitutive tyrosine phosphorylation of FOP-FGFR1. Phosphorylation of STAT1 and of STAT3, but not STAT5, is observed in cells expressing FOP-FGFR1. The survival function of FOP-FGFR1 is abrogated by mutation of the phospholipase C gamma binding site. Mitogen-activated protein kinase (MAPK) is also activated in FOP-FGFR1-expressing cells and confers cytokine-independent survival to hematopoietic cells. These results demonstrate that FOP-FGFR1 is capable of protecting cells from apoptosis by using the same effectors as the wild-type FGFR1. Furthermore, we show that FOP-FGFR1 phosphorylates phosphatidylinositol 3 (PI3)-kinase and AKT and that specific inhibitors of PI3-kinase impair its ability to promote cell survival. In addition, FOP-FGFR1-expressing cells show constitutive phosphorylation of the positive regulator of translation p70S6 kinase; this phosphorylation is inhibited by PI3-kinase and mTOR (mammalian target of rapamycin) inhibitors. These results indicate that translation control is important to mediate the cell survival effect induced by FOP-FGFR1. Finally, FOP-FGFR1 protects cells from apoptosis by survival signals including BCL2 overexpression and inactivation of caspase-9 activity. Elucidation of signaling events downstream of FOP-FGFR1 constitutive activation provides insight into the mechanism of leukemogenesis mediated by this oncogenic fusion protein.
FOP-成纤维细胞生长因子受体1（FGFR1）融合蛋白是由t(6;8)(q27;p12)易位导致的，该易位与一种伴有淋巴瘤、髓样增生和嗜酸性粒细胞增多的干细胞骨髓增殖性疾病相关。在本报告中，我们表明FOP富含亮氨酸的N端区域与FGFR1催化结构域的融合通过抗凋亡作用使小鼠造血细胞系Ba/F3转变为不依赖因子的细胞存活状态。这种存活效应依赖于FOP-FGFR1的组成型酪氨酸磷酸化。在表达FOP-FGFR1的细胞中观察到STAT1和STAT3的磷酸化，但未观察到STAT5的磷酸化。FOP-FGFR1的存活功能因磷脂酶Cγ结合位点的突变而被消除。丝裂原活化蛋白激酶（MAPK）在表达FOP-FGFR1的细胞中也被激活，并赋予造血细胞不依赖细胞因子的存活能力。这些结果表明，FOP-FGFR1能够通过与野生型FGFR1相同的效应器保护细胞免受凋亡。此外，我们表明FOP-FGFR1使磷脂酰肌醇3（PI3）激酶和AKT磷酸化，并且PI3激酶的特异性抑制剂损害其促进细胞存活的能力。此外，表达FOP-FGFR1的细胞显示翻译正调节因子p70S6激酶的组成型磷酸化；这种磷酸化被PI3激酶和雷帕霉素哺乳动物靶点（mTOR）抑制剂抑制。这些结果表明翻译控制对于介导FOP-FGFR1诱导的细胞存活效应很重要。最后，FOP-FGFR1通过包括BCL2过表达和caspase-9活性失活在内的存活信号保护细胞免受凋亡。对FOP-FGFR1组成型激活下游信号事件的阐明为这种致癌融合蛋白介导的白血病发生机制提供了见解。
