The WNT Pathway Is Relevant for the BCR-ABL1-Independent Resistance in Chronic Myeloid Leukemia

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/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 ( 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 vs. 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.

Tyrosine Kinase Inhibitors Play an Antiviral Action in Patients Affected by Chronic Myeloid Leukemia: A Possible Model Supporting Their Use in the Fight Against SARS-CoV-2

“…Moreover, about the low rate of TTV replication during treatment with nilotinib, we can hypothesize that some "antiviral" genes could be more expressed. In our previous study, we observed that imatinib upregulated two "antiviral" genes: Interferon-stimulated gene 15 (ISG15) and Mov10 RISC Complex RNA Helicase (MOV10) (67). ISG15 has been reported to exert a direct negative effect on viral replication, probably by restoring autophagy and sustaining NK proliferation and dendritic cell maturation (68).…”

Micro-RNA Biogenesis Genes (AGO1 and GEMIN4) Single Nucleotide Variants of Bad Prognosis and Poor Therapeutic Response in Egyptian Chronic Myeloid Leukemia Patients: Case–control Study

“…In addition, AGO1 regulates the transcription activity by stimulation of PI3K signaling [14]. Wnt pathway through PI3K signaling is involved in CML progression and therapeutic resistance [15]. This can give the basis of considering rs636832 as a bad prognostic as well poor therapeutic marker of CML in the present study.…”

“…As well AGO1 was found to regulate the transcription activity through stimulation of phosphoinositide 3-kinase (PI3K/AKT) [14]. Wnt pathway activation with subsequent PI3K/AKT signaling; is involved in CML progression and TKIs resistance [15]. Hence, AGO1 variants may participate in CML risk and prognosis.…”

Targeting Abnormal Hematopoietic Stem Cells in Chronic Myeloid Leukemia and Philadelphia Chromosome-Negative Classical Myeloproliferative Neoplasms

“…Porcupine (PORCN)-dependent acetylation of Wnt ligands is essential in Wnt/β-catenin signalling for maintenance of cellular functions [ 17 , 178 , 179 ]. BCR-ABL1 drives constitutive secretion of Wnt-ligands and overexpression of frizzled-4 (FZD4) receptors to promote nuclear transduction and stabilization of β-catenin, mediating TKI-resistance [ 178 , 179 , 180 ]. Riether et al proposed that it might be induced by prolonged TKI exposure as TKI-therapy depleted miR29 and amplified CD70 expression, leading to CD27-mediated Wnt activation for LSC quiescence and therapy resistance [ 181 ].…”