title: Down-regulation of CD20 expression in B-cell lymphoma cells after treatment with rituximab-containing combination chemotherapies: its prevalence and clinical significance.
abstract: 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 rebiopsy was performed in 19 patients. Of those 19, 5 (26.3%; diffuse large B-cell lymphoma [DLBCL], 3 cases; DLBCL transformed from follicular lymphoma, 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 reverse-transcription-polymerase chain reaction (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.
authors.affiliation: Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Hiraga
authors.forename: Akihiro
authors.initials: A
authors.lastname: Tomita
authors.forename: Takumi
authors.initials: T
authors.lastname: Sugimoto
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Shimada
authors.forename: Masafumi
authors.initials: M
authors.lastname: Ito
authors.forename: Shigeo
authors.initials: S
authors.lastname: Nakamura
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kiyoi
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kinoshita
authors.forename: Tomoki
authors.initials: T
authors.lastname: Naoe
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20 / Q000235:genetics* / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015536:Down-Regulation / Q000187:drug effects; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000502:physiology; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D016393:Lymphoma, B-Cell / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D011379:Prognosis; D012333:RNA, Messenger / Q000378:metabolism; D000069283:Rituximab; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D012333:RNA, Messenger; D000069283:Rituximab