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Open AccessArticle

Small Molecule Inhibitors of Microenvironmental Wnt/β-Catenin Signaling Enhance the Chemosensitivity of Acute Myeloid Leukemia

1
Section of Hematology, Stem Cell Research Laboratory, Department of Medicine, University of Verona, 37134 Verona, Italy
2
EA4340-BCOH, Biomarker in Cancerology and Onco-Haematology, Université de Versailles-Saint-Quentin-En-Yvelines, Université Paris Saclay, 92100 Boulogne-Billancourt, France
3
Department of Immunology, Erasmus University Medical Center, Doctor Molenwaterplein 40, 3015 GD Rotterdam, The Netherlands
4
Department of Oncology, Hematology Unit, Niguarda Hospital, 20162 Milan, Italy
5
Department of Health Sciences, University of Milan, 20146 Milan, Italy
6
Department of Diagnostics and Public Health, University and Hospital Trust of Verona, 37134 Verona, Italy
7
Fondazione Policlinico Universitario Gemelli, IRCCS, 00168 Roma, Italy
*
Author to whom correspondence should be addressed.
These authors contribute equally to this study.
Cancers 2020, 12(9), 2696; https://doi.org/10.3390/cancers12092696
Received: 5 September 2020 / Accepted: 17 September 2020 / Published: 21 September 2020
Considering the pivotal role of Wnt/β-catenin signaling in AML development and persistence, the current study addresses in AML, the prognostic value of Wnt/β-catenin signaling molecules and the anti-leukemic value of Wnt/β-catenin inhibition. In silico analysis of RNAseq data from AML patients and flow cytometric analysis of primary AML samples revealed that higher levels of Wnt/β-catenin pathway is a poor prognostic marker. Next, we found that pharmacological interference, through small molecule inhibitors of Wnt and/or GSK-3 signaling reduces AML cell survival by sensitizing the leukemia cells to chemotherapeutic agents both in vitro and in vivo. Overall, our findings suggested that Wnt-inhibitory therapy could overcome the prognostic significance of patient risk stratification, standing as a therapeutic response for all subgroups of AML.
Wnt/β-catenin signaling has been reported in Acute Myeloid leukemia, but little is known about its significance as a prognostic biomarker and drug target. In this study, we first evaluated the correlation between expression levels of Wnt molecules and clinical outcome. Then, we studied—in vitro and in vivo—the anti-leukemic value of combinatorial treatment between Wnt inhibitors and classic anti-leukemia drugs. Higher levels of β-catenin, Ser675-phospho-β-catenin and GSK-3α (total and Ser 9) were found in AML cells from intermediate or poor risk patients; nevertheless, patients presenting high activity of Wnt/β-catenin displayed shorter progression-free survival (PFS) according to univariate analysis. In vitro, many pharmacological inhibitors of Wnt signalling, i.e., LRP6 (Niclosamide), GSK-3 (LiCl, AR-A014418), and TCF/LEF (PNU-74654) but not Porcupine (IWP-2), significantly reduced proliferation and improved the drug sensitivity of AML cells cultured alone or in the presence of bone marrow stromal cells. In vivo, PNU-74654, Niclosamide and LiCl administration significantly reduced the bone marrow leukemic burden acting synergistically with Ara-C, thus improving mouse survival. Overall, our study demonstrates the antileukemic role of Wnt/β-catenin inhibition that may represent a potential new therapeutics strategy in AML. View Full-Text
Keywords: microenvironment; Wnt; AML; drug target microenvironment; Wnt; AML; drug target
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Takam Kamga, P.; Dal Collo, G.; Cassaro, A.; Bazzoni, R.; Delfino, P.; Adamo, A.; Bonato, A.; Carbone, C.; Tanasi, I.; Bonifacio, M.; Krampera, M. Small Molecule Inhibitors of Microenvironmental Wnt/β-Catenin Signaling Enhance the Chemosensitivity of Acute Myeloid Leukemia. Cancers 2020, 12, 2696.

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