Grassi Susanna, Palumbo Sara, Mariotti Veronica, Liberati Diego, Guerrini Francesca, Ciabatti Elena, Salehzadeh Serena, Baratè Claudia, Balducci Serena, Ricci Federica, Buda Gabriele, Iovino Lorenzo, Mazziotta Francesco, Ghio Francesco, Ercolano Giacomo, Di Paolo Antonello, Cecchettini Antonella, Baldini Chiara, Mattii Letizia, Pellegrini Silvia, Petrini Mario, Galimberti Sara
Hematology Division, University of Pisa, Pisa, Italy.
Department of Medical Biotechnologies, University of Siena, Siena, Italy.
Front Oncol. 2019 Jun 24;9:532. doi: 10.3389/fonc.2019.00532. eCollection 2019.
Notwithstanding the introduction of Tyrosine Kinase Inhibitors (TKIs) revolutionized the outcome of Chronic Myeloid Leukemia (CML), one third of patients still suspends treatment for failure response. Recent research demonstrated that several BCR/ABL1-independent mechanisms can sustain resistance, but the relationship between these mechanisms and the outcome has not yet been fully understood. This study was designed to evaluate in a "real-life" setting if a change of expression of several genes involved in the WNT/BETA-CATENIN, JAK-STAT, and POLYCOMB pathways might condition the outcome of CML patients receiving TKIs. Thus, the expression of 255 genes, related to the aforementioned pathways, was measured by quantitative PCR after 6 months of therapy and compared with levels observed at diagnosis in 11 CML patients, in order to find possible correlations with quality of response to treatment and event-free-survival (EFS). These results were then re-analyzed by the principal component method (PCA) for tempting to better cluster resistant cases. After 12 months of therapy, 6 patients achieved an optimal response and 5 were "resistant;" after application of both statistical methods, it was evident that in all pathways a significant overall up-regulation occurred, and that WNT was the pathway mostly responsible for the TKIs resistance. Indeed, 100% of patients with a "low" up-regulation of this pathway achieved an optimal response vs. 33% of those who showed a "high" gene over-expression ( = 0.016). Analogously, the 24-months EFS resulted significantly influenced by the degree of up-regulation of the WNT signaling: all patients with a "low" up-regulation were event-free vs. 33% of those who presented a "high" gene expression ( = 0.05). In particular, the PCA analysis confirmed the role of WNT pathway and showed that the most significantly up-regulated genes with negative prognostic value were DKK, WNT6, WISP1, and FZD8. In conclusion, our results sustain the need of a wide and multitasking approach in order to understand the resistance mechanisms in CML.
尽管酪氨酸激酶抑制剂（TKIs）的引入彻底改变了慢性髓性白血病（CML）的治疗结果，但仍有三分之一的患者因治疗反应不佳而中断治疗。最近的研究表明，几种不依赖BCR/ABL1的机制可维持耐药性，但这些机制与治疗结果之间的关系尚未完全明确。本研究旨在评估在“现实生活”环境中，参与WNT/β-连环蛋白、JAK-STAT和多梳蛋白途径的几种基因的表达变化是否会影响接受TKIs治疗的CML患者的治疗结果。因此，在治疗6个月后，通过定量PCR检测了与上述途径相关的255个基因的表达，并与11例CML患者诊断时观察到的水平进行比较，以寻找与治疗反应质量和无事件生存期（EFS）的可能相关性。然后通过主成分分析法（PCA）对这些结果进行重新分析，试图更好地对耐药病例进行聚类。治疗12个月后，6例患者获得了最佳反应，5例为“耐药”；应用两种统计方法后，很明显在所有途径中均出现了显著的总体上调，且WNT途径是导致TKIs耐药的主要途径。事实上，该途径“低”上调的患者中有100%获得了最佳反应，而基因“高”表达的患者中这一比例为33%（P = 0.016）。类似地，WNT信号上调程度对24个月的EFS有显著影响：所有“低”上调的患者均无事件发生，而基因“高”表达的患者中这一比例为33%（P = 0.05）。特别是，PCA分析证实了WNT途径的作用，并表明具有负面预后价值的上调最显著的基因是DKK、WNT6、WISP1和FZD8。总之，我们的结果支持需要采用广泛且多任务的方法来理解CML的耐药机制。
