The Wnt/β-catenin signaling is an evolutionarily conserved pathway that plays a pivotal role in the regulation of cell differentiation and self-renewal. It is considered one of the main components of the hematopoiesis and its impairment can lead to the development of acute myeloid leukemia (AML). In the last years, it was reported that human bone marrow mesenchymal stromal cells (hBM-MSCs) support the growth and chemoresistance of leukemia cells, but their contribution to Wnt/β-catenin signaling in AML cells is still unclear. In this study, we first analyzed the expression pattern of Wnt/β-catenin components and their correlation with the clinical outcome of AML patients, observing high expression levels of β-catenin and its active form (phospho-Ser675) in intermediate and poor-risk groups of patients. Accordingly, patients with a lower activation of Wnt/β-catenin signaling showed longer progression-free survival. Then, we demonstrated that hBM-MSCs increase the activity of nuclear β-catenin in blast cells, suggesting that Wnt signaling could be involved in the crosstalk between bone marrow stroma and leukemia cells. Therefore, we investigated the anti-leukemia effects of pharmacological Wnt (Niclosamide and PNU-74654) or GSK-3 (LiCl and AR-A014418) inhibitors in combination or not with classic anti-leukemia drugs (Ara-C and Idarubicin). In vitro, Wnt/GSK-3 inhibitors significantly reduced cell proliferation and cell viability, improving drug sensitivity of AML cells cultured alone or in presence of hMB-MSCs. In vivo, PNU-74654, Niclosamide, and LiCl, acting synergistically with Ara-C, dramatically reduced the engraftment of human CD45+ leukemic cells, thus improving animal survival. In conclusion, our results suggest that β-catenin could be useful as a prognostic marker for AML patients and its inhibition could represent a new potential therapeutic strategy to improve patient outcome and to overcome the chemoresistance mediated by tumor microenvironment.
|Titolo:||The Wnt/β-catenin Signaling: A Microenvironmental Support To Chemoresistance In Acute Myeloid Leukemia|
|Data di pubblicazione:||2021|
|Appare nelle tipologie:||07.13 Doctoral Thesis|