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// Paul Takam Kamga 1 , Giada Dal Collo 1 , Giulio Bassi 1 , Martina Midolo 1 , Massimo Delledonne 2, 3 , Marco Chilosi 4 , Massimiliano Bonifacio 1 and Mauro Krampera 1 1 Stem Cell Research Laboratory, Section of Hematology, Department of Medicine, University of Verona, Verona, Italy 2 Department of Biotechnology, University of Verona, Verona, Italy 3 Personal Genomics S.R.L., Verona, Italy 4 Section of Pathology, Department of Diagnostics and Public Health, University of Verona, Verona, Italy Correspondence to: Mauro Krampera, email: mauro.krampera@univr.it Keywords: Notch signaling; B-acute lymphoblastic leukemia; B-ALL; Alagille syndrome; ALGS Received: January 02, 2018 Accepted: March 11, 2018 Published: April 06, 2018 ABSTRACT Notch signaling contribution to B-cell acute lymphoblastic leukemia (B-ALL) development is still under investigation. The serendipitous onset of B-ALL in a patient affected by the germinal Notch mutation-dependent Alagille syndrome allowed us to establish a B-ALL cell line (VR-ALL) bearing a genetic loss of function in components of Notch signaling. VR-ALL is a common-type B-ALL cell line, grows in conventional culture medium supplemented with 10% serum, and gives rise, once injected into immunodeficient NOG mice, to a mouse xenograft model of B-ALL. Exome sequencing revealed deleterious mutations in some components of Notch signaling, including Jagged1, Notch1, and Notch2. In addition, VR-ALL is sensitive both in vitro and in vivo to γ-secretase inhibitors (GSIs) as well as conventional anti-leukemic drugs. For all these reasons, VR-ALL may help to gain more insights into the role of Notch signaling in B-ALL.

// 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.