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