Department of Biochemistry, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Montebello, N-0310 Oslo, Norway.
Cell Signal. 2011 Nov;23(11):1758-66. doi: 10.1016/j.cellsig.2011.06.010. Epub 2011 Jun 30.
The KG-1a cell line is developed from a human stem cell myeloproliferative neoplasm as the result of intragenic disruption and a chromosomal translocation of the FGFR1 gene and the FGFR1OP2 gene encoding a protein of unknown function called FOP2 (FGFR1 Oncogene Partner 2). The resulting fusion protein FOP2-FGFR1 is soluble and has constitutive tyrosine kinase activity. Since the heat shock protein HSP90 and its co-chaperone CDC37 have been shown to stabilize many oncogenic proteins, we investigated the requirement for HSP90 or HSP90-CDC37 assistance to maintain the stability or activity of FOP2-FGFR1 expressed in KG-1a cells. We found that HSP90-CDC37 forms a permanent complex with FOP2-FGFR1. This results in protection against degradation of FOP2-FGFR1 and holds the oncoprotein in a permanently active conformation. Inhibition of HSP90 or depletion of CDC37 or heat shock factor 1 (HSF1) reduced the expression level of FOP2-FGFR1 and was sufficient to block the oncoprotein induced proliferation of KG-1a cells. We conclude that the driver of malignancy in KG-1a leukemic cells, FOP2-FGFR1, is an HSP90 addicted oncoprotein. This provides a rationale for the therapeutic use of HSP90 inhibitors in myeloid leukemias that contain FGFR fusion proteins.
KG-1a 细胞系源自人类干细胞骨髓增生性肿瘤，是 FGFR1 基因和 FGFR1OP2 基因（编码一种未知功能蛋白 FOP2 的基因）内基因中断和染色体易位的结果。由此产生的融合蛋白 FOP2-FGFR1 是可溶性的，具有组成性酪氨酸激酶活性。由于热休克蛋白 HSP90 及其共伴侣 CDC37 已被证明能稳定许多致癌蛋白，因此我们研究了 HSP90 或 HSP90-CDC37 协助维持在 KG-1a 细胞中表达的 FOP2-FGFR1 的稳定性或活性的必要性。我们发现 HSP90-CDC37 与 FOP2-FGFR1 形成永久性复合物。这导致 FOP2-FGFR1 免受降解，并使致癌蛋白保持永久激活构象。抑制 HSP90 或耗尽 CDC37 或热休克因子 1（HSF1）会降低 FOP2-FGFR1 的表达水平，并足以阻断 FOP2-FGFR1 诱导的 KG-1a 细胞增殖。我们得出结论，KG-1a 白血病细胞恶性的驱动因素，FOP2-FGFR1，是一种 HSP90 成瘾的致癌蛋白。这为在含有 FGFR 融合蛋白的髓系白血病中使用 HSP90 抑制剂提供了一个合理的依据。
