title: Notch signalling drives bone marrow stromal cell-mediated chemoresistance in acute myeloid leukemia.
abstract: Both preclinical and clinical investigations suggest that Notch signalling is critical for the development of many cancers and for their response to chemotherapy. We previously showed that Notch inhibition abrogates stromal-induced chemoresistance in lymphoid neoplasms. However, the role of Notch in acute myeloid leukemia (AML) and its contribution to the crosstalk between leukemia cells and bone marrow stromal cells remain controversial. Thus, we evaluated the role of the Notch pathway in the proliferation, survival and chemoresistance of AML cells in co-culture with bone marrow mesenchymal stromal cells expanded from both healthy donors (hBM-MSCs) and AML patients (hBM-MSCs*). As compared to hBM-MSCs, hBM-MSCs* showed higher level of Notch1, Jagged1 as well as the main Notch target gene HES1. Notably, hBM-MSCs* induced expression and activation of Notch signalling in AML cells, supporting AML proliferation and being more efficientin inducing AML chemoresistance than hBM-MSCs*. Pharmacological inhibition of Notch using combinations of Notch receptor-blocking antibodies or gamma-secretase inhibitors (GSIs), in presence of chemotherapeutic agents, significant lowered the supportive effect of hBM-MSCs and hBM-MSCs* towards AML cells, by activating apoptotic cascade and reducing protein level of STAT3, AKT and NF-κB.These results suggest that Notch signalling inhibition, by overcoming the stromal-mediated promotion of chemoresistance,may represent a potential therapeutic targetnot only for lymphoid neoplasms, but also for AML.
authors.affiliation: Stem Cell Research Laboratory, Section of Hematology, Department of Medicine, University of Verona, Verona, Italy.
authors.forename: Paul
authors.initials: P
authors.lastname: Takam Kamga
authors.affiliation: Stem Cell Research Laboratory, Section of Hematology, Department of Medicine, University of Verona, Verona, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Bassi
authors.affiliation: Stem Cell Research Laboratory, Section of Hematology, Department of Medicine, University of Verona, Verona, Italy.
authors.forename: Adriana
authors.initials: A
authors.lastname: Cassaro
authors.affiliation: Stem Cell Research Laboratory, Section of Hematology, Department of Medicine, University of Verona, Verona, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Midolo
authors.affiliation: Stem Cell Research Laboratory, Section of Hematology, Department of Medicine, University of Verona, Verona, Italy.
authors.forename: Mariano
authors.initials: M
authors.lastname: Di Trapani
authors.affiliation: Stem Cell Research Laboratory, Section of Hematology, Department of Medicine, University of Verona, Verona, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Gatti
authors.affiliation: Stem Cell Research Laboratory, Section of Hematology, Department of Medicine, University of Verona, Verona, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Carusone
authors.affiliation: Stem Cell Research Laboratory, Section of Hematology, Department of Medicine, University of Verona, Verona, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Resci
authors.affiliation: Stem Cell Research Laboratory, Section of Hematology, Department of Medicine, University of Verona, Verona, Italy.
authors.forename: Omar
authors.initials: O
authors.lastname: Perbellini
authors.affiliation: Division of Hematology, Ca' Foncello Hospital, Treviso, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Gottardi
authors.affiliation: Stem Cell Research Laboratory, Section of Hematology, Department of Medicine, University of Verona, Verona, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Bonifacio
authors.affiliation: Department of Biomedical Sciences, University of Ngaoundere-Cameroon, Cameroon.
authors.forename: Armel Hervé
authors.initials: AH
authors.lastname: Nwabo Kamdje
authors.affiliation: Stem Cell Research Laboratory, Section of Hematology, Department of Medicine, University of Verona, Verona, Italy.
authors.forename: Achille
authors.initials: A
authors.lastname: Ambrosetti
authors.affiliation: Stem Cell Research Laboratory, Section of Hematology, Department of Medicine, University of Verona, Verona, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Krampera
mesh_terms: D000208:Acute Disease; D000328:Adult; D000368:Aged; D001854:Bone Marrow Cells / Q000378:metabolism*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018920:Coculture Techniques; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D018922:HL-60 Cells; D006801:Humans; D020014:K562 Cells; D007951:Leukemia, Myeloid / Q000378:metabolism* / Q000473:pathology; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D008875:Middle Aged; D009842:Oligopeptides / Q000494:pharmacology; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D020298:U937 Cells
chemical_list: D009842:Oligopeptides; D051880:Receptors, Notch; C523462:benzyloxycarbonyl-leucyl-leucyl-norleucinal
keywords: AML; MSC; Notch; chemoresistance