title: Bone marrow stromal cells protect lymphoma B-cells from rituximab-induced apoptosis and targeting integrin α-4-β-1 (VLA-4) with natalizumab can overcome this resistance.
abstract: Rituximab improves the outcome of patients with non-Hodgkin lymphoma, but does not completely eradicate residual B-cell populations in the microenvironment of the bone marrow and lymph nodes. Adhesion to stromal cells can protect B-cells from apoptosis induced by chemotherapy drugs [(cell adhesion-mediated drug resistance (CAM-DR)]. A similar mechanism of resistance to rituximab has not, to our knowledge, been described. We tested the hypothesis that the microenvironment protects malignant B-cells from rituximab-induced apoptosis, and that blocking these interactions with natalizumab, an antibody targeting VLA-4 (integrin alfa-4-beta-1/CD49d), can overcome this protection. VLA-4 is an adhesion molecule constitutively expressed on malignant B-cells and is important for pro-survival signalling in the bone marrow and lymph node microenvironment. The human bone marrow stromal cell line HS-5 was shown to strongly protect B-cell lymphoma cells from rituximab cytotoxicity, suggesting the existence of a stromal cell adhesion-mediated antibody resistance (CAM-AR) mechanism analogous to CAM-DR. Natalizumab decreased B-lymphocyte adherence to fibronectin by 75-95% and partially overcame stromal protection against rituximab and cytotoxic drugs. These pre-clinical findings suggest that the addition of stromal adhesion-disruptive drugs to rituximab-containing therapy could improve treatment efficacy.
authors.affiliation: Division of Hematology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Marek
authors.initials: M
authors.lastname: Mraz
authors.forename: Clive S
authors.initials: CS
authors.lastname: Zent
authors.forename: Amy K
authors.initials: AK
authors.lastname: Church
authors.forename: Diane F
authors.initials: DF
authors.lastname: Jelinek
authors.forename: Xiaosheng
authors.initials: X
authors.lastname: Wu
authors.forename: Sarka
authors.initials: S
authors.lastname: Pospisilova
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Ansell
authors.forename: Anne J
authors.initials: AJ
authors.lastname: Novak
authors.forename: Neil E
authors.initials: NE
authors.lastname: Kay
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Witzig
authors.forename: Grzegorz S
authors.initials: GS
authors.lastname: Nowakowski
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001402:B-Lymphocytes / Q000187:drug effects / Q000502:physiology; D001854:Bone Marrow Cells / Q000502:physiology; D002448:Cell Adhesion / Q000187:drug effects; D018920:Coculture Techniques; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors / Q000502:physiology; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000473:pathology*; D000069442:Natalizumab; D000069283:Rituximab; D017154:Stromal Cells / Q000502:physiology*; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D039041:Integrin alpha4beta1; D000069442:Natalizumab; D000069283:Rituximab