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Bone marrow stromal cells protect lymphoma B-cells from rituximab-induced apoptosis and targeting integrin ?-4-?-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.

SUBMITTER: Mraz M

PROVIDER: S-EPMC4405035 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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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.

Mraz Marek M Zent Clive S CS Church Amy K AK Jelinek Diane F DF Wu Xiaosheng X Pospisilova Sarka S Ansell Stephen M SM Novak Anne J AJ Kay Neil E NE Witzig Thomas E TE Nowakowski Grzegorz S GS

British journal of haematology 20110712 1

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-cel ...[more]

PMID: 21749361

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Dataset Information

Bone marrow stromal cells protect lymphoma B-cells from rituximab-induced apoptosis and targeting integrin ?-4-?-1 (VLA-4) with natalizumab can overcome this resistance.

Publications

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.

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