Bone marrow stromal cells protect lymphoma B-cells from rituximab-induced apoptosis and targeting integrin alfa-4-beta-1 (VLA4) with natalizumab can overcome this resistance

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Authors

MRÁZ Marek ZENT Clive CHURCH Amy JELINEK Diane WU Xiaosheng POSPÍŠILOVÁ Šárka ANSELL Stephen NOVAK Anne KAY Neil WITZIG Thomas NOWAKOWSKI Grzegorz

Year of publication 2011
Type Article in Periodical
Magazine / Source British Journal of Haematology
MU Faculty or unit

Central European Institute of Technology

Citation
Web http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2011.08794.x/abstract
Doi http://dx.doi.org/10.1111/j.1365-2141.2011.08794.x
Field Oncology and hematology
Keywords lymphoma; stromal cells; cell adhesion-mediated drug resistance; rituximab; natalizumab
Description 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.
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