Submitted August 19, 2008
Accepted February 25, 2009
Down-regulation of CD20 expression in B-cell lymphoma cells after treatment with rituximab-containing combination chemotherapies: its prevalence and clinical significance
Junji Hiraga, Akihiro Tomita*, Takumi Sugimoto, Kazuyuki Shimada, Masafumi Ito, Shigeo Nakamura, Hitoshi Kiyoi, Tomohiro Kinoshita, and Tomoki Naoe
Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan
Department of Pathology, Nagoya Red-Cross First Hospital, Nagoya, Japan
Department of Pathology and Clinical Laboratories, Nagoya University Hospital, Nagoya, Japan
Department of Infectious Diseases, Nagoya University School of Medicine, Nagoya, Japan
* Corresponding author; email: atomita{at}med.nagoya-u.ac.jp.
Although rituximab is a key molecular targeting drug for CD20-positive B-cell lymphomas, resistance to rituximab has recently been recognized as a considerable problem. Here we report that a CD20-negative phenotypic change after chemotherapies with rituximab occurs in a certain number of CD20-positive B-cell lymphoma patients. For 5 years, 124 patients with B-cell malignancies were treated with rituximab-containing chemotherapies in Nagoya University Hospital. Relapse or progression was confirmed in 36 patients (29.0%), and a re-biopsy was performed in 19 patients. Of those 19, 5 (26.3%) (DLBCL; 3 cases, and DLBCL transformed from FL; 2 cases) indicated CD20 protein-negative transformation. Despite salvage chemotherapies without rituximab, all 5 patients died within 1 year of the CD20-negative transformation. Quantitative RT-PCR showed that CD20 mRNA expression was significantly lower in CD20-negative cells than in CD20-positive cells obtained from the same patient. Interestingly, when CD20-negative cells were treated with 5-aza-2'-deoxycytidine in vitro, the expression of CD20 mRNA was stimulated within 3 days, resulting in the restoration of both cell surface expression of the CD20 protein and rituximab sensitivity. These findings suggest that some epigenetic mechanisms may be partly related to the down-regulation of CD20 expression after rituximab treatment.
