title: Cross-talk between chronic lymphocytic leukemia (CLL) tumor B cells and mesenchymal stromal cells (MSCs): implications for neoplastic cell survival.
abstract: Leukemic cells from Chronic Lymphocytic Leukemia (CLL) patients interact with stromal cells of the surrounding microenvironment. Mesenchymal Stromal Cells (MSCs) represent the main population in CLL marrow stroma, which may play a key role for disease support and progression. In this study we evaluated whether MSCs influence in vitro CLL cell survival. MSCs were isolated from the bone marrow of 46 CLL patients and were characterized by flow cytometry analysis. Following co-culture of MSCs and leukemic B cells, we demonstrated that MSCs were able to improve leukemic B cell viability, this latter being differently dependent from the signals coming from MSCs. In addition, we found that the co-culture of MSCs with leukemic B cells induced an increased production of IL-8, CCL4, CCL11, and CXCL10 chemokines.As far as drug resistance is concerned, MSCs counteract the cytotoxic effect of Fludarabine/Cyclophosphamide administration in vivo, whereas they do not protect CLL cells from the apoptosis induced by the kinase inhibitors Bafetinib and Ibrutinib. The evidence that leukemic clones are conditioned by environmental stimuli suggest new putative targets for therapy in CLL patients.
authors.affiliation: Padua University School of Medicine, Department of Medicine, Hematology and Clinical Immunology Branch, Padua, Italy.|Venetian Institute of Molecular Medicine (VIMM), Padua, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Trimarco
authors.affiliation: Padua University School of Medicine, Department of Medicine, Hematology and Clinical Immunology Branch, Padua, Italy.|Venetian Institute of Molecular Medicine (VIMM), Padua, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Ave
authors.affiliation: Padua University School of Medicine, Department of Medicine, Hematology and Clinical Immunology Branch, Padua, Italy.|Venetian Institute of Molecular Medicine (VIMM), Padua, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Facco
authors.affiliation: Padua University School of Medicine, Department of Medicine, Hematology and Clinical Immunology Branch, Padua, Italy.|Venetian Institute of Molecular Medicine (VIMM), Padua, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Chiodin
authors.affiliation: Padua University School of Medicine, Department of Medicine, Hematology and Clinical Immunology Branch, Padua, Italy.|Venetian Institute of Molecular Medicine (VIMM), Padua, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Frezzato
authors.affiliation: Padua University School of Medicine, Department of Medicine, Hematology and Clinical Immunology Branch, Padua, Italy.|Venetian Institute of Molecular Medicine (VIMM), Padua, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Martini
authors.affiliation: Padua University School of Medicine, Department of Medicine, Hematology and Clinical Immunology Branch, Padua, Italy.|Venetian Institute of Molecular Medicine (VIMM), Padua, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Gattazzo
authors.affiliation: Padua University School of Medicine, Department of Medicine, Hematology and Clinical Immunology Branch, Padua, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Lessi
authors.affiliation: Padua University School of Medicine, Department of Medicine, Hematology and Clinical Immunology Branch, Padua, Italy.
authors.forename: Carlo Alberto
authors.initials: CA
authors.lastname: Giorgi
authors.affiliation: Padua University School of Medicine, Department of Medicine, Hematology and Clinical Immunology Branch, Padua, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Visentin
authors.affiliation: Padua University School of Medicine, Department of Medicine, Hematology and Clinical Immunology Branch, Padua, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Castelli
authors.affiliation: Padua University School of Medicine, Department of Medicine, Hematology and Clinical Immunology Branch, Padua, Italy.|Venetian Institute of Molecular Medicine (VIMM), Padua, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Severin
authors.affiliation: Padua University School of Medicine, Department of Medicine, Hematology and Clinical Immunology Branch, Padua, Italy.|Venetian Institute of Molecular Medicine (VIMM), Padua, Italy.
authors.forename: Renato
authors.initials: R
authors.lastname: Zambello
authors.affiliation: Padua University School of Medicine, Department of Medicine, Hematology and Clinical Immunology Branch, Padua, Italy.|Venetian Institute of Molecular Medicine (VIMM), Padua, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Piazza
authors.affiliation: Padua University School of Medicine, Department of Medicine, Hematology and Clinical Immunology Branch, Padua, Italy.|Venetian Institute of Molecular Medicine (VIMM), Padua, Italy.
authors.forename: Gianpietro
authors.initials: G
authors.lastname: Semenzato
authors.affiliation: Padua University School of Medicine, Department of Medicine, Hematology and Clinical Immunology Branch, Padua, Italy.|Venetian Institute of Molecular Medicine (VIMM), Padua, Italy.
authors.forename: Livio
authors.initials: L
authors.lastname: Trentin
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology*; D002450:Cell Communication; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D003520:Cyclophosphamide / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D006801:Humans; D015151:Immunoblotting; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism / Q000473:pathology*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology*; D008875:Middle Aged; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D014740:Vidarabine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D003520:Cyclophosphamide; D014740:Vidarabine; D000225:Adenine; C506918:bafetinib; C024352:fludarabine
keywords: chronic lymphocytic leukemia; kinase inhibitors; mesenchymal stromal cells