Drube Julia, Ernst Thomas, Pfirrmann Markus, Albert Benadict Vincent, Drube Sebastian, Reich Daniela, Kresinsky Anne, Halfter Kathrin, Sorio Claudio, Fabisch Christian, Hochhaus Andreas, Böhmer Frank-D
Institut für Molekulare Zellbiologie, CMB, Universitätsklinikum Jena, Jena, Germany.
Abteilung Hämatologie und Internistische Onkologie, Klinik für Innere Medizin II, Universitätsklinikum Jena, Jena, Germany.
Oncotarget. 2018 Jan 15;9(10):9442-9455. doi: 10.18632/oncotarget.24253. eCollection 2018 Feb 6.
The introduction of second-generation tyrosine kinase inhibitors (TKIs) targeting the protein-tyrosine kinase (PTK) BCR-ABL1 has improved treatment response in chronic myeloid leukemia (CML). However, in some patients response still remains suboptimal. Protein-tyrosine phosphatases (PTPs) are natural counter-actors of PTK activity and can affect TKI sensitivity, but the impact of PTPs on treatment response to second-generation TKIs is unknown. We assessed the mRNA expression level of 38 PTPs in 66 newly diagnosed CML patients and analyzed the potential relation with treatment outcome after 9 months of nilotinib medication. A significantly positive association with response was observed for higher PTPN13, PTPRA, PTPRC (also known as CD45), PTPRG, and PTPRM expression. Selected PTPs were then subjected to a functional analysis in CML cell line models using PTP gene knockout by CRISPR/Cas9 technology or PTP overexpression. These analyses revealed PTPRG positively and PTPRC negatively modulating nilotinib response. Consistently, PTPRG negatively and PTPRC positively affected BCR-ABL1 dependent transformation. We identified BCR-ABL1 signaling events, which were affected by modulating PTP levels or nilotinib treatment in the same direction. In conclusion, the PTP status of CML cells is important for the response to second generation TKIs and may help in optimizing therapeutic strategies.
靶向蛋白酪氨酸激酶（PTK）BCR-ABL1的第二代酪氨酸激酶抑制剂（TKIs）的引入改善了慢性髓性白血病（CML）的治疗反应。然而，在一些患者中，反应仍然不尽人意。蛋白酪氨酸磷酸酶（PTPs）是PTK活性的天然拮抗因子，可影响TKI敏感性，但PTPs对第二代TKIs治疗反应的影响尚不清楚。我们评估了66例新诊断CML患者中38种PTPs的mRNA表达水平，并分析了尼罗替尼用药9个月后与治疗结果的潜在关系。观察到较高的PTPN13、PTPRA、PTPRC（也称为CD45）、PTPRG和PTPRM表达与反应呈显著正相关。然后，使用CRISPR/Cas9技术敲除PTP基因或过表达PTP，在CML细胞系模型中对选定的PTPs进行功能分析。这些分析显示PTPRG正向调节、PTPRC负向调节尼罗替尼反应。一致地，PTPRG负向影响、PTPRC正向影响BCR-ABL1依赖性转化。我们确定了BCR-ABL1信号事件，其受到以相同方向调节PTP水平或尼罗替尼治疗的影响。总之，CML细胞的PTP状态对第二代TKIs的反应很重要，可能有助于优化治疗策略。
