Mutation or polymorphism of the CD20 gene is not associated with the response to R-CHOP in diffuse large B cell lymphoma patients

Sar, Aylin; Perizzolo, Marco; Stewart, D. A.; Mansoor, Adnan; DiFrancesco, Lisa M.; Demetrick, Douglas J.

doi:10.1016/j.leukres.2008.10.013

Cited by 22 publications

(17 citation statements)

References 22 publications

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“…21,41,43,44 More recently, deletions/ mutations were described within the C-term region of the CD20, 21 but no previous study identified the presence of this alternative ⌬CD20 transcript. Thus, we report here another possible phenomenon of RTX resistance associated with CD20 gene splicing and ⌬CD20 expression.…”

Section: Discussionmentioning

confidence: 99%

Identification of an alternative CD20 transcript variant in B-cell malignancies coding for a novel protein associated to rituximab resistance

Henry

Deschamps

Rohrlich

et al. 2010

Blood

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Human CD20 is a B-cell lineage-specific marker expressed by normal and leukemic B cells from the pre-B to the plasmacell stages and is a target for rituximab (RTX) immunotherapy. A CD20 reverse transcriptase-polymerase chain reaction (PCR) on B-cell lines cDNA yielded a short PCR product (⌬CD20) corresponding to a spliced mRNA transcript linking the exon 3 and exon 7 ends. We established here that this novel, alternatively spliced CD20 transcript is expressed and detectable at various levels in leukemic B cells, lymphoma B cells, in vivo tonsil-or in vitro CD40L-activated B cells, and Epstein-Barr virus (EBV)-transformed B cells, but not in resting CD19 ؉ -or CD20 ؉ -sorted B cells from peripheral blood or bone marrow of healthy donors. The truncated CD20 sequence is within the reading frame, codes a protein of 130 amino acids (ϳ 15-17 kDa) lacking large parts of the 4 transmembrane segments, suggesting that ⌬CD20 is a nonanchored membrane protein. We demonstrated the translation into a ⌬CD20 protein which is associated with the membrane CD20 protein and showed its involvement in RTX resistance. Study of patient samples before and after RTX resistance or escape confirms our in vitro findings. (Blood. 2010;115:2420-2429) Introduction CD20 (MS4A1) is a 33-to 37-kDa nonglycosylated transmembrane (TM) phosphoprotein that is widely expressed throughout B-lymphocyte ontogeny, in normal or malignant B cells. 1 The 16-kb gene encoding human CD20, consisting of 8 exons, has been mapped to chromosome 11 (11q12-q13) and belongs to the MS4A (membrane spanning 4A) gene family localized within a cluster of related genes (MS4A1 to MS4A11). 2 Its transcription leads to 3 mRNA isoforms: a dominant 2.8-kb transcript, using exons 1 to 8; a second exon 1-spliced transcript shorter by 263 bp; and a third, minor 3.4-kb transcript, 3 all encoding a full-length CD20 protein.The CD20 protein consists of cytoplasmic N-and C-termini and 4 hydrophobic regions for anchoring the molecule in the membrane. 4 A total of 3 isoforms have been identified, including a predominant 33-kDa molecule and 2 isoforms of 34.5 and 36 kDa, resulting from differential phosphorylation states (on serine and threonine residues) in relation to B-cell stimulation and proliferation. 5 CD20 appears to play a role in Ca ϩϩ conductance 6 and is also involved in cell-cycle progression by interaction with src family kinases. 7 Finally, CD20 circulating form has been identified in chronic lymphocytic leukemia (CLL), Hodgkin disease, or nonHodgkin lymphoma (NHL), and in healthy persons. 8 CD20 expression at the cell surface of malignant B cells makes it a target for monoclonal antibody (mAb) therapy. Rituximab (RTX), the first US Food and Drug Administration (FDA)-approved mAb for clinical therapy, targets the CD20 antigen 9 and leads to CD20-expressing B-cell depletion through different mechanisms 9,10 (for review, see Cartron et al 11 ). Thus, RTX is widely used against B-cell malignancies and also for autoimmune diseases such as rheumatoid arthritis, 12 steroid refract...

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Section: Discussionmentioning

confidence: 99%

Identification of an alternative CD20 transcript variant in B-cell malignancies coding for a novel protein associated to rituximab resistance

Henry

Deschamps

Rohrlich

et al. 2010

Blood

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“…Although clinical and laboratory data on this issue are lacking, different HLA/KIR genotypes or different concentrations of KIR ligands (31) could impart different thresholds of activation to the NK cell repertoire, and thus might influence both the ADCC and CR3-ADCC response to rituximab. To date, there is no evidence that inherited mutations or polymorphisms of the CD20 gene lead to a poor response to rituximab (39,61).…”

Section: Host-related Originsmentioning

confidence: 99%

Interindividual Variability of Response to Rituximab: From Biological Origins to Individualized Therapies

Cartron

Trappe

Solal‐Céligny

et al. 2011

Clinical Cancer Research

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Rituximab has markedly changed the treatment of B-cell malignancies. Despite its widespread use, however, its precise mode of action and the impact of host-and tumor-related factors on rituximabactivated biological pathways were only recently clarified. Biological mechanisms resulting in complete resistance to rituximab may exist at both the cellular and subcellular level; however, their frequency and their impact on clinical response are unclear. The identification of Fcg receptor polymorphisms that can influence anti-CD20 antibody activity has resulted in the development of third-generation anti-CD20 antibodies. However, it is also now appreciated that pharmacokinetic variability is a major factor affecting clinical response to anti-CD20 antibodies. The concept of antigenic mass, which takes into account the total tumor load and the expression levels of the target antigen CD20, is able to explain the correlation between rituximab plasma concentrations and treatment responses. Thus, it can be hypothesized that dosing regimens that take this information into account will help to improve response rates.

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“…None of the studies were confirmatory in nature, and those are the only ones in which clinical application can be found. Schreck et al [75] demonstrate that a large number of Th2 cells in HL is related to better survival; Dong et al [76] show that bcl10 expression (next to t (11;14)) is related to HP-eradication unresponsiveness; according to Wang et al [77], cytoplasmic sox11-expressing MCLs have a poorer survival; mutation nor polymorphism of the CD20 gene is predicting rituximab response (Sar et al [78]); Aktas et al [79] show that high apoptotic index is related to good prognosis in pediatric lymphomas; Lenz et al [80] describes new gene signatures that predict therapy response in DLBL; Peh et al [81] found that bcl-6 expression is associated with poor survival in DLBL and immunohistochemically determined ABC not; according to Johnson et al [82], DLBL with low CD20 expression have lower survival rate; Ki67 and Pim1 are independent indicators of poor survival in MCL (Hsi et al [83]); low Ki67 is a negative predictor of survival in DLBL (Hasselblom et al [84]); SIRT1 expression is associated with poor prognosis in DLBL (Jang et al [85]); in FL, Johnson et al [86] show that secondary genetic alterations indicate aggressive behavior; Hasselblom et al [87] show that the number of CD68-positive cells in DLBL does not predict prognosis; TCL1A is associated with more aggressive clinical behavior in CLL and MCL according to Aggarwal et al [88]; aberrations in the MYC locus are associated with poor outcome in DLBL (Klapper et al [89] and Yoon et al [90]); expression of P-glycoprotein indicates therapy unresponsiveness in nasal type NK/T cell lymphoma according to Wang et al [91];…”

Section: Prognostic Factors In Lymphomamentioning

confidence: 99%

New developments in the pathology of malignant lymphoma. A review of the literature published from August 2013 to December 2013

Krieken

2014

J Hematopathol

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Mutation or polymorphism of the CD20 gene is not associated with the response to R-CHOP in diffuse large B cell lymphoma patients

Cited by 22 publications

References 22 publications

Identification of an alternative CD20 transcript variant in B-cell malignancies coding for a novel protein associated to rituximab resistance

Identification of an alternative CD20 transcript variant in B-cell malignancies coding for a novel protein associated to rituximab resistance

Interindividual Variability of Response to Rituximab: From Biological Origins to Individualized Therapies

New developments in the pathology of malignant lymphoma. A review of the literature published from August 2013 to December 2013

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