Down-regulation of CD20 expression in B-cell lymphoma cells after treatment with rituximab-containing combination chemotherapies: its prevalence and clinical significance

Hiraga, Junji; Tomita, Akihiro; Sugimoto, Takumi; Shimada, Kazuyuki; Ito, Masafumi; Nakamura, Shigeo; Kiyoi, Hitoshi; Kinoshita, Tomohiro; Naoe, Tomoki

doi:10.1182/blood-2008-08-175208

Cited by 221 publications

(200 citation statements)

References 44 publications

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“…Loss of CD20 and other B-cell marker expression has been associated with more aggressive clinical behavior and poor prognosis. 12,13 However, this loss of B-cell markers has not previously been described in association with the uniform strong CD30 expression that was seen in our case.…”

Section: Commentmentioning

confidence: 39%

Transformation of Small B-Cell Lymphoma Into Large Cell CD30+, CD4+, Epstein-Barr Virus–Negative Lymphoma

Shaver

Schwarting

et al. 2014

Archives of Pathology &Amp; Laboratory Medicine

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We report here 2 separate cases in which patients with known low-grade B-cell lymphomas presented with transformed lesions that were CD30 þ , CD4 þ , Epstein-Barr virus negative, and negative or focally weak for a wide range of B-cell, T-cell, and histiocytic/dendritic cell markers. In each case the transformed lymphoma possessed an identical pattern of immunoglobulin heavy chain and/or BCL2 rearrangement to the corresponding original lowgrade B-cell lymphoma, confirming their identity as transformed B-cell lymphoma. A review of the relevant literature reveals that, to our knowledge, no transformed B-cell lymphomas with this immunophenotype have been previously reported, which creates the opportunity for potential errors of diagnosis. These cases highlight the importance of correlation with the patient's history and with molecular genetic results in rendering an accurate diagnosis.

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Section: Commentmentioning

confidence: 39%

Transformation of Small B-Cell Lymphoma Into Large Cell CD30+, CD4+, Epstein-Barr Virus–Negative Lymphoma

Shaver

Schwarting

et al. 2014

Archives of Pathology &Amp; Laboratory Medicine

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“…3,4 There are two emerging issues to be resolved for better usage of this drug: weak effects on some tumors [6][7][8] and drug resistance. 5,[9][10][11] In this study, we clearly demonstrated that HDAC inhibitors, VPA and romidepsin, potentiated the cytotoxic effect of rituximab against Burkitt lymphoma, which has innate resistance to rituximab, 7 by enhancing the expression of surface CD20 antigen both in vitro and in vivo. We also analyzed the mechanisms of CD20 upregulation and found that HDAC inhibitors acetylated core histones of CD20 promoter to enhance the binding of Sp1, leading to transactivation of the CD20 gene in BJA-B and Namalwa cells.…”

Section: Discussionmentioning

confidence: 83%

“…8 Furthermore, several cases of CD20-negative relapse were identified after treatment with rituximab-based regimens in diffuse large B-cell lymphoma. 9,10 Recently, Hiraga et al 11 reported that relapse or disease progression was observed in B30% of patients with B-cell lymphomas treated with rituximab-containing chemotherapies, and CD20 expression was lost in 5 of 19 relapsed patients who underwent repeated biopsy. It is of note that DNAdemethylating agents restored CD20 expression in lymphoma cells isolated from these patients, suggesting that epigenetic mechanisms underlie the downregulation of CD20 after rituximab treatment.…”

Section: Introductionmentioning

confidence: 99%

HDAC inhibitors augment cytotoxic activity of rituximab by upregulating CD20 expression on lymphoma cells

et al. 2010

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Anti-CD20 antibody rituximab is now essential for the treatment of CD20-positive B-cell lymphomas. Decreased expression of CD20 is one of the major mechanisms underlying both innate and acquired resistance to rituximab. In this study, we show that histone deacetylase (HDAC) inhibitors augment the cytotoxic activity of rituximab by enhancing the surface expression of CD20 antigen on lymphoma cells. HDAC inhibitors, valproic acid (VPA) and romidepsin, increased CD20 expression at protein and mRNA levels in B-cell lymphoma cell lines with relatively low CD20 expression levels. The VPA-mediated increase in CD20 expression occurred at 1 mM, which is clinically achievable and safe, but insufficient for inducing cell death. Chromatin immunoprecipitation assays revealed that HDAC inhibitors transactivated the CD20 gene through promoter hyperacetylation and Sp1 recruitment. HDAC inhibitors potentiated the activity of rituximab in complementdependent cytotoxic assays. In mouse lymphoma models, HDAC inhibitors enhanced CD20 expression along with histone hyperacetylation in transplanted cells, and acted synergistically with rituximab to retard their growth. The combination with HDAC inhibitors may serve as an effective strategy to overcome rituximab resistance in B-cell lymphomas.

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“…The mechanism of such resistance has not been fully elucidated, however, a number of reports on the potential mechanisms of resistance after rituximab mono-therapy or R-CHOP combination therapy have been suggested. These include loss or down-regulation of CD20 membrane expression, histological transformation and up-regulation of anti-apoptotic molecules including bcl-2 (29)(30)(31)(32). We are currently examining whether BM-ca, alone or in combination with chemotherapy, exerts an activity, not seen with rituximab, on rituximabresistant B-NHL cell lines.…”

Section: Discussionmentioning

confidence: 99%

BM-ca is a newly defined type I/II anti-CD20 monoclonal antibody with unique biological properties

Nishida

Uematsu²,

Kobayashi³

et al. 2011

Int J Oncol

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Abstract. Rituximab (chimeric anti-CD20 mAb) is currently used in the treatment of B-NHL and B cell malignancies, alone or in combination with chemotherapy. However, subsets of patients do not initially respond and/or develop resistance to additional treatments. Hence, there is a need to develop more effective anti-CD20 mAbs that may improve clinical response. BM-ca is a novel humanized anti-CD20 mAb that was tested against several B-NHL cell lines and was compared to several anti-CD20 mAbs (Rituximab, ofatumumab, 2H7, B1 and B-Ly1). BM-ca was shown to strongly induce both homotypic cell aggregation and redistribution of CD20 to membrane lipid rafts. BM-ca was also able to induce programmed cell death (apoptosis) without the need for cross-linking and demonstrated potent complement-dependent cytotoxicity (CDC). BM-ca was more cytotoxic than rituximab even in malignant B cells expressing low amounts of membrane CD20. Type I anti-CD20 mAbs typically induce minimal levels of homotypic cell aggregation and apoptosis but strong localization of CD20 to lipid rafts and potent CDC. Type II anti-CD20 mAbs typically exert the reverse activities. Noteworthy, BM-ca exhibits properties that are shared by both type I and type II anti-CD20 mAbs, which may reflect the recognition of a new CD20 epitope and/or exhibit different molecular signaling. Overall, the present data show that BM-ca is a novel anti-CD20 mAb that may be classified as a type I/II. The therapeutics efficacy of BM-ca awaits its use in clinical trials. IntroductionThe use of rituximab as a single agent or in combination with cyclophosphamide, hydroxydaunorubicin, oncovin and prednisone (CHOP), is now a standard therapy for nonHodgkin's lymphoma (NHL) (1,2). NHL patients do not always completely respond to rituximab therapy, however, and a subset of patients who initially responded become resistant or less responsive to further treatment (3). Despite a great number of reports, the in vivo mechanisms responsible to predict the clinical outcome in NHL after anti-CD20 treatment remain elusive. Complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) and apoptosis are all potential cytotoxic mechanisms, although it is unclear which mechanism is important in vivo. Redistribution of CD20 to membrane lipid rafts by anti-CD20 results in the clustering of antibody molecules and enhancing C1q binding, the first step in the CDC induction mechanism (4). In addition to these above cytotoxic mechanisms, homotypic cell aggregation has been reported to be involved in antibody-induced cytotoxicity as well as the induction of apoptosis (5-7).CD20 antibodies have been classified as type I or type II depending on their functional characteristics. Type I exhibits strong CDC activity but weak apoptosis whereas type II shows the opposite, i.e., weak CDC and strong apoptosis. Type I antibodies have the ability to redistribute CD20 to membrane lipid rafts whereas type II do not. Further, type I induce little homotypic cell aggregation whereas homotypic ce...

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Down-regulation of CD20 expression in B-cell lymphoma cells after treatment with rituximab-containing combination chemotherapies: its prevalence and clinical significance

Cited by 221 publications

References 44 publications

Transformation of Small B-Cell Lymphoma Into Large Cell CD30+, CD4+, Epstein-Barr Virus–Negative Lymphoma

Transformation of Small B-Cell Lymphoma Into Large Cell CD30+, CD4+, Epstein-Barr Virus–Negative Lymphoma

HDAC inhibitors augment cytotoxic activity of rituximab by upregulating CD20 expression on lymphoma cells

BM-ca is a newly defined type I/II anti-CD20 monoclonal antibody with unique biological properties

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