In vivo model of follicular lymphoma resistant to rituximab.
OBJECTIVE
Follicular lymphoma (FL) is the most common subtype of indolent lymphomas. Rituximab is widely used alone or in combination therapy for the treatment of FL. Despite its well-established clinical efficacy, a subpopulation of patients does not respond to rituximab and most patients will relapse after therapy. The mechanisms of action and resistance to rituximab are not fully understood.


METHODS
To study these mechanisms we developed an in vivo model of FL resistant to rituximab. This model was developed using the human RL line, isolated from a patient with FL, grown as xenotransplants in severe combined immunodeficient mice, exposed weekly to rituximab in vivo, followed by serial reimplantation and reexposure to rituximab, until a resistant phenotype was obtained.


RESULTS
RL-derived tumors unexposed to rituximab were grown as controls and compared with the resistant tumors. Although the expression of CD46 and CD55 antigens were not differently expressed in the resistant cells, the complement inhibitor CD59 was overexpressed in a subpopulation and CD20 was found to be expressed at a lower level in a minority of cells. Bcl-X(L) and YY1 were also found more highly expressed in rituximab-resistant cells.


CONCLUSIONS
This model provides insight on potential in vivo resistance mechanisms to rituximab and could help contribute to the development of novel therapies in rituximab-refractory diseases.
Dalle
Stéphane
S
Université Claude Bernard de Lyon, Institut National de la Sante et de la Recherche Medicale, U590, Laboratoire de Cytologie Analytique, Faculte de Medecine Rockefeller, Lyon, France. stephane.dalle@chu-lyon.fr
Dupire
Sophie
S
Brunet-Manquat
Stéphanie
S
Reslan
Lina
L
Plesa
Adriana
A
Dumontet
Charles
C
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D058846:Antibodies, Monoclonal, Murine-Derived; D017209:Apoptosis; D045744:Cell Line, Tumor; D002470:Cell Survival; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008224:Lymphoma, Follicular / Q000188:drug therapy*; D051379:Mice; D016513:Mice, SCID; D000069283:Rituximab; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000069283:Rituximab