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

Br J Haematol. 2011 Oct;155(1):53-64. doi: 10.1111/j.1365-2141.2011.08794.x. Epub 2011 Jul 12.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal, Humanized / pharmacology
  • Antibodies, Monoclonal, Murine-Derived / pharmacology*
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Apoptosis / physiology
  • B-Lymphocytes / drug effects
  • B-Lymphocytes / physiology
  • Bone Marrow Cells / physiology
  • Cell Adhesion / drug effects
  • Coculture Techniques
  • Drug Resistance, Neoplasm / drug effects
  • Humans
  • Integrin alpha4beta1 / antagonists & inhibitors
  • Integrin alpha4beta1 / physiology
  • Lymphoma, B-Cell / drug therapy
  • Lymphoma, B-Cell / pathology*
  • Natalizumab
  • Rituximab
  • Stromal Cells / physiology*
  • Tumor Cells, Cultured
  • Tumor Microenvironment / drug effects


  • Antibodies, Monoclonal, Humanized
  • Antibodies, Monoclonal, Murine-Derived
  • Antineoplastic Agents
  • Integrin alpha4beta1
  • Natalizumab
  • Rituximab