Isotype switch variants reveal clonally related subpopulations in diffuse large B-cell lymphoma

Blood ◽  
2000 ◽  
Vol 96 (7) ◽  
pp. 2550-2556
Author(s):  
Christian H. Ottensmeier ◽  
Freda K. Stevenson
Keyword(s):  
B Cell ◽  
Somatic Mutation ◽  
Variable Region ◽  
B Cell Lymphoma ◽  
Immunohistochemical Analysis ◽  
Protein Levels ◽  
The Status ◽  
Aggressive Tumors ◽  
Variable Region Genes ◽  
Large B Cell

Primary diffuse large B-cell lymphomas (DLBCLs) are aggressive tumors accounting for approximately 40% of B-cell malignancies. The immunoglobulin (Ig) variable region genes have undergone rearrangement and are commonly somatically mutated. The majority show intraclonal variation which indicates that somatic mutation has continued after transformation. Typically, cells of DLBCLs express Ig of a single isotype, but there may be accompanying cells that express alternative isotypes. To probe the status of the isotype switch process in DLBCL, 4 cases of tumor-derived constant region transcripts of all isotypes were investigated. Following the identification of the VDJ sequences, the presence of the major isotype expected from immunohistochemical analysis was confirmed at the RNA level. Another 3-4 alternative isotypes were revealed in all cases, some of which could also be detected by immunohistochemistry. All cases were somatically mutated with an intraclonal variation. In 2 cases there were clearly distinct patterns of somatic mutation between isotypes, which was consistent with independent evolution of the tumor subpopulations. There was apparent clustering of mutational patterns into either an IgMD/IgG3/IgA set or an IgG1/IgA set, indicating that the switch to IgA can occur by different routes. Alternative isotype expression is evident in DLBCL at both the RNA and protein levels. The pattern of mutation indicates that switching is occurring in subpopulations of the tumor after malignant transformation. The findings support the concept that isotype switch events may be a feature of DLBCL.

Isotype switch variants reveal clonally related subpopulations in diffuse large B-cell lymphoma

Blood ◽  
2000 ◽  
Vol 96 (7) ◽  
pp. 2550-2556 ◽  
Author(s):  
Christian H. Ottensmeier ◽  
Freda K. Stevenson
Keyword(s):  
B Cell ◽  
Somatic Mutation ◽  
Variable Region ◽  
B Cell Lymphoma ◽  
Immunohistochemical Analysis ◽  
Protein Levels ◽  
The Status ◽  
Aggressive Tumors ◽  
Variable Region Genes ◽  
Large B Cell

Abstract Primary diffuse large B-cell lymphomas (DLBCLs) are aggressive tumors accounting for approximately 40% of B-cell malignancies. The immunoglobulin (Ig) variable region genes have undergone rearrangement and are commonly somatically mutated. The majority show intraclonal variation which indicates that somatic mutation has continued after transformation. Typically, cells of DLBCLs express Ig of a single isotype, but there may be accompanying cells that express alternative isotypes. To probe the status of the isotype switch process in DLBCL, 4 cases of tumor-derived constant region transcripts of all isotypes were investigated. Following the identification of the VDJ sequences, the presence of the major isotype expected from immunohistochemical analysis was confirmed at the RNA level. Another 3-4 alternative isotypes were revealed in all cases, some of which could also be detected by immunohistochemistry. All cases were somatically mutated with an intraclonal variation. In 2 cases there were clearly distinct patterns of somatic mutation between isotypes, which was consistent with independent evolution of the tumor subpopulations. There was apparent clustering of mutational patterns into either an IgMD/IgG3/IgA set or an IgG1/IgA set, indicating that the switch to IgA can occur by different routes. Alternative isotype expression is evident in DLBCL at both the RNA and protein levels. The pattern of mutation indicates that switching is occurring in subpopulations of the tumor after malignant transformation. The findings support the concept that isotype switch events may be a feature of DLBCL.

scholarly journals Diffuse Large B-Cell Lymphoma: Recognition of Markers for Targeted Therapy

Hemato ◽  
2021 ◽  
Vol 2 (2) ◽  
pp. 281-304
Author(s):  
Laura Tomas-Roca ◽  
Marta Rodriguez ◽  
Ruth Alonso-Alonso ◽  
Socorro M. Rodriguez-Pinilla ◽  
Miguel Angel Piris
Keyword(s):  
Targeted Therapy ◽  
B Cells ◽  
B Cell ◽  
B Cell Lymphoma ◽  
Therapeutic Approaches ◽  
Molecular Features ◽  
Molecular Variants ◽  
The Status ◽  
Underlying Causes ◽  
Large B Cell

Diffuse large B-cell lymphomas (DLBCL)s, the most common type of Non-Hodgkin’s Lymphoma, constitute a heterogeneous group of disorders including different disease sites, strikingly diverse molecular features and a profound variability in the clinical behavior. Molecular studies and clinical trials have partially revealed the underlying causes for this variability and have made possible the recognition of some molecular variants susceptible of specific therapeutic approaches. The main histogenetic groups include the germinal center, activated B cells, thymic B cells and terminally differentiated B cells, a basic scheme where the large majority of DLBCL cases can be ascribed. The nodal/extranodal origin, specific mutational changes and microenvironment peculiarities provide additional layers of complexity. Here, we summarize the status of the knowledge and make some specific proposals for addressing the future development of targeted therapy for DLBC cases.

Acquisition of potential N-glycosylation sites in the immunoglobulin variable region by somatic mutation is a distinctive feature of follicular lymphoma

Blood ◽  
2002 ◽  
Vol 99 (7) ◽  
pp. 2562-2568 ◽  
Author(s):  
Delin Zhu ◽  
Helen McCarthy ◽  
Christian H. Ottensmeier ◽  
Peter Johnson ◽  
Terry J. Hamblin ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
B Cell ◽  
Somatic Mutation ◽  
Germinal Center ◽  
Variable Region ◽  
B Cell Lymphoma ◽  
Single Chain ◽  
Single Chain Fv ◽  
Glycosylation Sites ◽  
Vh Genes

Most patients with follicular lymphoma (FL) have somatically mutated V genes with intraclonal variation, consistent with location in the germinal center site. Using our own and published sequences, we have investigated the frequency of potential N-glycosylation sites introduced into functional VH genes as a consequence of somatic mutation. FL cells were compared with normal memory B cells or plasma cells matched for similar levels of mutation. Strikingly, novel sites were detected in 55 of 70 (79%) patients with FL, compared to 7 of 75 (9%) in the normal B-cell population (P < .001). Diffuse large B-cell lymphoma (DLCL) showed an intermediate frequency (13 of 32 [41%] patients). Myeloma and the mutated subset of chronic lymphocytic leukemia showed frequencies similar to those of normal cells in 5 of 64 (8%) patients and 5 of 40 (13%) patients, respectively. In 3 of 3 random patients with FL, immunoglobulin was expressed as recombinant single-chain Fv inPichia pastoris, and glycosylation was demonstrated. These findings indicate that N-glycosylation of the variable region may be common in FL and in a subset of DLCL. Most novel sites are located in the complementarity-determining regions. VH sequences of nonfunctional VH genes contained few sites, arguing for positive selection in FL. One possibility is that the added carbohydrate in the variable region contributes to interaction with elements in the germinal center environment. This common feature of FL may be critical for tumor behavior.

scholarly journals MicroRNA-181a Inhibits Activated B-Cell-Like Diffuse Large B-Cell Lymphoma Progression by Repressing CARD11

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Danxia Zhu ◽  
Cheng Fang ◽  
Wenting He ◽  
Chen Wu ◽  
Xiaodong Li ◽  
...  
Keyword(s):  
B Cell ◽  
Binding Site ◽  
Cell Lines ◽  
Expression Vector ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Wild Type ◽  
Protein Levels ◽  
Large B Cell Lymphoma ◽  
Large B Cell

We investigated the role of miR-181a in diffuse large B-cell lymphoma (DLBCL) and its potential target genes. miR-181a levels were lower in activated B-cell- (ABC-) like DLBCL cells than that in germinal center B-cell- (GCB-) like DLBCL cells. Overexpression of miR-181a in ABC-like DLBCL cell lines (OCI-LY10 and U2932) resulted in G0/G1 cell cycle arrest, increased apoptosis, and decreased invasiveness. miRNA target prediction programs (miRanda, TargetScan, and miRDB) identified caspase recruitment domain-containing protein 11 (CARD11) as a putative miR-181a target. CARD11 mRNA and protein levels were higher in the ABC-like DLBCL than that in GCB-like DLBCL. Moreover, CARD11 mRNA and protein levels were downregulated in the OCI-LY10 and U2932 cell lines overexpressing miR-181a. Dual luciferase reporter assays confirmed the miR-181a binding site in the CARD11 3′UTR region. OCI-LY10 and U2932 cells transfected with a CARD11 expression vector encoding miR-181a with a mutated binding site showed higher CARD11 protein levels, cell viability, G2/M phase cells, and invasiveness compared to those transfected with a wild-type CARD11 expression vector. Nude mice xenografted with OCI-LY10 cells with overexpressed wild-type miR-181a generated smaller tumors compared to those with overexpressed mutated binding site of CARD11 3′UTR and miR-181a. These results indicate that miR-181a inhibits ABC-like DLBCL by repressing CARD11.

scholarly journals Favored use of immunoglobulin V(H)4 Genes in AIDS-associated B-cell lymphoma

Blood ◽  
1996 ◽  
Vol 88 (1) ◽  
pp. 252-260 ◽  
Author(s):  
A Bessudo ◽  
V Cherepakhin ◽  
TA Johnson ◽  
LZ Rassenti ◽  
E Feigal ◽  
...  
Keyword(s):  
B Cell ◽  
Heavy Chain ◽  
Variable Region ◽  
B Cell Lymphoma ◽  
Acquired Immunodeficiency ◽  
Somatic Diversification ◽  
Immunodeficiency Syndrome ◽  
Variable Region Genes ◽  
Ig Heavy Chain ◽  
Complementarity Determining Region

Abstract We examined the lg heavy chain variable region genes (Ig V(H) genes) expressed in biopsy specimens of 10 patients with acquired immunodeficiency syndrome (AIDS)-associated lymphoma. Eight expressed Ig V(H) genes of the V(H)4 group, indicating a bias toward expression of Ig V(H) genes of this subgroup. Sequence analyses of Ig V(H) genes isolated from any one lymphoma did not reveal evidence for intraclonal diversity. However, some lymphomas express Ig V(H) genes that apparently have undergone somatic diversification and selection. In addition, we found that the sequence encoding each examined third complementarity determining region most likely resulted from D-D fusion, a process that ordinarily contributes to the generation of a relatively small proportion of the Ig heavy chain genes expressed by normal adult B cells. The noted restriction in the use of Ig V(H) genes by AIDS-associated B-cell lymphomas suggests that antigenic stimulation contributes to lymphomagenesis in patients with AIDS.

scholarly journals De Novo CD5+ Diffuse Large B-Cell Lymphomas Express VH Genes With Somatic Mutation

Blood ◽  
1998 ◽  
Vol 91 (4) ◽  
pp. 1145-1151 ◽  
Author(s):  
Masanori Taniguchi ◽  
Kouji Oka ◽  
Atsunori Hiasa ◽  
Motoko Yamaguchi ◽  
Toshiyuki Ohno ◽  
...  
Keyword(s):  
B Cell ◽  
De Novo ◽  
Cell Lymphoma ◽  
Variable Region ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Cellular Origin ◽  
Vh Gene ◽  
Vh Genes ◽  
Large B Cell

Abstract To clarify the cellular origin of de novo CD5+ diffuse large B-cell lymphoma (CD5+ DLBL), particularly in comparison with other CD5+ B-cell neoplasms such as chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), we analyzed the nucleotide sequence of the Ig heavy chain variable region (IgVH) genes of de novo CD5+ DLBL cases. All 4 cases examined had extensive somatic mutations in contrast with CLL or MCL. The VH gene sequences of de novo CD5+ DLBL displayed 86.9% to 95.2% homology with the corresponding germlines, whereas those of simultaneously analyzed CLL and MCL displayed 97.6% to 100% homology. The VH family used was VH3 in 1 case, VH4 in 2 cases, and VH5 in 1 case. In 2 of 4 examined cases, the distribution of replacement and silent mutations over the complementarity determining region and framework region in the VH genes was compatible with the pattern resulting from the antigen selection. Clinically, CD5+DLBL frequently involved a variety of extranodal sites (12/13) and lymph node (11/13). Immunophenotypically, CD5+ DLBL scarcely expressed CD21 and CD23 (3/13 and 2/13, respectively). These findings indicate that de novo CD5+ DLBL cells are derived from a B-1 subset distinct from those of CLL or MCL.

Unmutated Ig VH Genes Are Associated With a More Aggressive Form of Chronic Lymphocytic Leukemia

Blood ◽  
1999 ◽  
Vol 94 (6) ◽  
pp. 1848-1854 ◽  
Author(s):  
Terry J. Hamblin ◽  
Zadie Davis ◽  
Anne Gardiner ◽  
David G. Oscier ◽  
Freda K. Stevenson
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Somatic Mutation ◽  
Variable Region ◽  
Lymphocytic Leukemia ◽  
Cell Of Origin ◽  
Trisomy 12 ◽  
Vh Gene ◽  
Vh Genes ◽  
Variable Region Genes

Abstract Despite having several characteristics of naı̈ve B cells, chronic lymphocytic leukemia (CLL) cells have been shown in some cases to have somatically mutated Ig variable region genes, indicating that the cell of origin has passed through the germinal center. A previous study of patients with CLL found an association between lack of somatic mutation and trisomy 12 and, therefore, possibly with a less favorable prognosis. We have sequenced the Ig VH genes of the tumor cells of 84 patients with CLL and correlated our findings with clinical features. A total of 38 cases (45.2%) showed ≥ 98% sequence homology with the nearest germline VH gene; 46 cases (54.8%) showed >2% somatic mutation. Unmutated VH genes were significantly associated with V1-69 and D3-3 usage, with atypical morphology; isolated trisomy 12, advanced stage and progressive disease. Survival was significantly worse for patients with unmutated VH genes irrespective of stage. Median survival for stage A patients with unmutated VH genes was 95 months compared with 293 months for patients whose tumors had mutated VHgenes (P = .0008). The simplest explanation is that CLL comprises 2 different diseases with different clinical courses. One, arising from a memory B cell, has a benign course, the other, arising from a naı̈ve B cell, is more malignant.

scholarly journals Primary Diffuse Large B Cell Lymphoma Mimicking Hyperplastic Reactive Lesion (Lymphoma of the Oral Cavity)

2018 ◽  
Vol 2018 ◽  
pp. 1-4
Author(s):  
Liziane Cattelan Donaduzzi ◽  
Angélica Reinheimer ◽  
Maria Augusta Ramires da Silva ◽  
Lucia de Noronha ◽  
Aline Cristina Batista Rodrigues Johann ◽  
...  
Keyword(s):  
Oral Cavity ◽  
B Cell ◽  
Cell Lymphoma ◽  
Histopathological Examination ◽  
B Cell Lymphoma ◽  
Immunohistochemical Analysis ◽  
Lymphoid Cells ◽  
Anterior Teeth ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Objective. To report a case of a challenging oral diagnosis involving a primary diffuse large B cell lymphoma of the oral cavity mimicking a hyperplastic reactive lesion.Case Report. A 72-year-old male patient was referred to the Department of Stomatology presenting a proliferative nodular lesion in the anterior region of the mandible involving the anterior teeth. The clinical examination revealed anterior teeth affected by periodontal disease, suggesting the nodular cession hyperplastic reaction. Incisional biopsy was performed under local anesthesia. The histopathological examination revealed a diffuse proliferation of atypical large lymphoid cells. The tumor cells showed immunopositivity for CD20 and Ki67 (100%) and negativity for CD3, CD30, and CD15. The diagnosis of diffuse large B cell lymphoma was established. The patient underwent chemotherapy and progressed to death after nine months.Conclusion. Lymphomas of the oral cavity are rare and may have nonspecific clinical features, mimicking inflammatory and reactive lesions. Therefore, a detailed clinical evaluation associated with histopathological and immunohistochemical analysis should be performed to enable early and accurate diagnoses in suspected oral lesions.

scholarly journals Favored use of immunoglobulin V(H)4 Genes in AIDS-associated B-cell lymphoma

Blood ◽  
1996 ◽  
Vol 88 (1) ◽  
pp. 252-260 ◽  
Author(s):  
A Bessudo ◽  
V Cherepakhin ◽  
TA Johnson ◽  
LZ Rassenti ◽  
E Feigal ◽  
...  
Keyword(s):  
B Cell ◽  
Heavy Chain ◽  
Variable Region ◽  
B Cell Lymphoma ◽  
Acquired Immunodeficiency ◽  
Somatic Diversification ◽  
Immunodeficiency Syndrome ◽  
Variable Region Genes ◽  
Ig Heavy Chain ◽  
Complementarity Determining Region

We examined the lg heavy chain variable region genes (Ig V(H) genes) expressed in biopsy specimens of 10 patients with acquired immunodeficiency syndrome (AIDS)-associated lymphoma. Eight expressed Ig V(H) genes of the V(H)4 group, indicating a bias toward expression of Ig V(H) genes of this subgroup. Sequence analyses of Ig V(H) genes isolated from any one lymphoma did not reveal evidence for intraclonal diversity. However, some lymphomas express Ig V(H) genes that apparently have undergone somatic diversification and selection. In addition, we found that the sequence encoding each examined third complementarity determining region most likely resulted from D-D fusion, a process that ordinarily contributes to the generation of a relatively small proportion of the Ig heavy chain genes expressed by normal adult B cells. The noted restriction in the use of Ig V(H) genes by AIDS-associated B-cell lymphomas suggests that antigenic stimulation contributes to lymphomagenesis in patients with AIDS.

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