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/BETACATENIN, 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 versus 33% of those who showed a “high” gene over-expression (p=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 versus 33% of those who presented a “high” gene expression (p=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.

The WNT pathway is relevant for the BCR-ABL1-independent resistance in chronic myeloid leukemia

Susanna Grassi;Sara Palumbo;Veronica Mariotti;Francesca Guerrini;Elena Ciabatti;Federica Ricci;Gabriele Buda;Francesco Mazziotta;Antonello Di Paolo;Antonella Cecchettini;Chiara Baldini;Letizia Mattii;Silvia Pellegrini;Mario Petrini;Sara Galimberti.
2019-01-01

Abstract

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/BETACATENIN, 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 versus 33% of those who showed a “high” gene over-expression (p=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 versus 33% of those who presented a “high” gene expression (p=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.
2019
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, Fracesco; Ercolano, Giacomo; DI PAOLO, Antonello; Cecchettini, Antonella; Baldini, Chiara; Mattii, Letizia; Pellegrini, Silvia; Petrini, Mario; Galimberti, Sara
File in questo prodotto:
File Dimensione Formato  
frontiers in oncology_09_532.pdf

accesso aperto

Tipologia: Versione finale editoriale
Licenza: Creative commons
Dimensione 1.35 MB
Formato Adobe PDF
1.35 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11568/991656
Citazioni
  • ???jsp.display-item.citation.pmc??? 6
  • Scopus 12
  • ???jsp.display-item.citation.isi??? 9
social impact