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

Marek Mraz, Clive S. Zent, Amy K. Church, Diane F. Jelinek, Xiaosheng Wu, Sarka Pospisilova, Stephen M. Ansell, Anne J. Novak, Neil E. Kay, Thomas E. Witzig, Grzegorz S. Nowakowski

Research output: Contribution to journalArticlepeer-review

74 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)53-64
Number of pages12
JournalBritish journal of haematology
Volume155
Issue number1
DOIs
StatePublished - Oct 2011

Keywords

  • Cell adhesion-mediated drug resistance
  • Lymphoma
  • Natalizumab
  • Rituximab
  • Stromal cells

ASJC Scopus subject areas

  • Hematology

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