Notch signalling drives bone marrow stromal cell-mediated chemoresistance in acute myeloid leukemia

// Paul Takam Kamga 1 , Giulio Bassi 1 , Adriana Cassaro 1 , Martina Midolo 1 , Mariano Di Trapani 1 , Alessandro Gatti 1 , Roberta Carusone 1 , Federica Resci 1 , Omar Perbellini 1 , Michele Gottardi 2 , Massimiliano Bonifacio 1 , Armel Herve Nwabo Kamdje 3 , Achille Ambrosetti 1 and Mauro Krampera 1 1 Stem Cell Research Laboratory, Section of Hematology, Department of Medicine, University of Verona, Verona, Italy 2 Division of Hematology, Ca’ Foncello Hospital, Treviso, Italy 3 Department of Biomedical Sciences, University of Ngaoundere-Cameroon, Cameroon Correspondence to: Mauro Krampera, email: // Keywords : AML, MSC, Notch, chemoresistance Received : February 10, 2016 Accepted : February 25, 2016 Published : March 07, 2016 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.