TRB

Gene Summary

Gene:TRB; T-cell receptor beta locus
Aliases: TCRB, TRB@
Location:7q34
Summary:T cell receptors recognize foreign antigens which have been processed as small peptides and bound to major histocompatibility complex (MHC) molecules at the surface of antigen presenting cells (APC). Each T cell receptor is a dimer consisting of one alpha and one beta chain or one delta and one gamma chain. In a single cell, the T cell receptor loci are rearranged and expressed in the order delta, gamma, beta, and alpha. If both delta and gamma rearrangements produce functional chains, the cell expresses delta and gamma. If not, the cell proceeds to rearrange the beta and alpha loci. This region represents the germline organization of the T cell receptor beta locus. The beta locus includes V (variable), J (joining), diversity (D), and C (constant) segments. During T cell development, the beta chain is synthesized by a recombination event at the DNA level joining a D segment with a J segment; a V segment is then joined to the D-J gene. The C segment is later joined by splicing at the RNA level. Recombination of many different V segments with several J segments provides a wide range of antigen recognition. Additional diversity is attained by junctional diversity, resulting from the random additional of nucleotides by terminal deoxynucleotidyltransferase. Several V segments and one J segment of the beta locus are known to be incapable of encoding a protein and are considered pseudogenes. The beta locus also includes eight trypsinogen genes, three of which encode functional proteins and five of which are pseudogenes. Chromosomal abnormalities involving the T-cell receptor beta locus have been associated with T-cell lymphomas. [provided by RefSeq, Jul 2008]
Databases:HGNC, GeneCard, Gene
Source:NCBIAccessed: 15 March, 2017

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 15 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Thymus Gland
  • Chromosome 7
  • Sezary Syndrome
  • Gene Expression Profiling
  • T-Cell Lymphoma
  • Cancer Gene Expression Regulation
  • Childhood Cancer
  • T-Lymphocyte Gene Rearrangement
  • p53 Protein
  • T-Lymphocytes
  • Adult T-Cell Leukemia-Lymphoma
  • Genes, Immunoglobulin
  • TRG
  • Leukaemia
  • Biomarkers, Tumor
  • Clone Cells
  • Skin Cancer
  • Cutaneous T-cell lymphoma
  • FISH
  • Receptors, Antigen, T-Cell, alpha-beta
  • Adolescents
  • Melanoma
  • Residual Disease
  • T-Cell Antigen Receptors
  • Acute Lymphocytic Leukaemia
  • Southern Blotting
  • Genetic Recombination
  • Base Sequence
  • Molecular Sequence Data
  • Reproducibility of Results
  • NOTCH1
  • T-Cell Leukemia
  • Gene Rearrangement
  • Immunophenotyping
  • Immunohistochemistry
  • Genes, T-Cell Receptor alpha
  • Flow Cytometry
  • Beta-Chain T-Cell Antigen Receptor Gene Rearrangement
  • TRB
  • Cancer DNA
  • Complementarity Determining Regions
  • Polymerase Chain Reaction
Tag cloud generated 15 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: TRB (cancer-related)

Sun BG, Zhang L, Xiang T, et al.
[Effects of Jianpi Jiedu Recipe on TCRVβCDR3 Spectratyping of Liver Cancer Rats with Pi Deficiency Syndrome].
Zhongguo Zhong Xi Yi Jie He Za Zhi. 2016; 36(6):735-43 [PubMed] Related Publications
OBJECTIVE: To observe anti-cancer effects of Jianpi Jiedu Recipe (JJR) on liver cancer (LC) rats with Pi deficiency syndrome (PDS) and its relation with the third complementary-determining region gene spectratyping of TCRVβ-chain (TCRVβCDR3).
METHODS: Rats were divided into 8 groups according to random digit table, i.e., the blank control group (normal), the PDS group, the LC model group, the LC-PDS group, high, middle, and low dose JJR groups (75.00, 37.50, 18.75 g/kg, respectively by gastrogavage, once per day), the thymus pentapeptide group (5 mg/kg, intramuscular injection, twice per week), 8 in each group. Rats in the normal group were administered with physiological saline by gastrogavage once per day. PDS rat model was prepared by bitter-cold purgation. LC model was prepared by orthotopic transplantation method. Twenty gene subfamilies of TCRβCDR3 in the thymus, liver, and LC tissues were detected by Gene Scan.
RESULTS: High and middle dose JJR could postpone the growth of LC volume (P < 0.05), with equivalent liver index and thymus index to those of the normal group (P > 0.05). In thymus and liver tissue of the normal group, the number of clones (20 and 19), gene fragment number (220 and 113), Quasi-Gaussian distribution ratio of TCRVβCDR3 gene repertoire (100.0% and 42.1%), and fragment fluorescence peak area (6,539 ± 2,325 and 1,238 ± 439) were at the highest level among the 8 groups. TCRVβCDR3 expressions in thymus and liver tissue of high and middle dose JJR groups were approximate to those of the normal group. They were in the middle of the thymus pentapeptide group, the PDS group, the LC model group, and poorest in the LC-PDS group. TCRVβCDR3 in liver tissue expressed the best in the thymus pentapeptide group.
CONCLUSION: JJR might inhibit the growth of LC cells, and its mechanism might be related to enhancing TCRVβCDR3 spectratype expression.

Ruggiero E, Nicolay JP, Fronza R, et al.
High-resolution analysis of the human T-cell receptor repertoire.
Nat Commun. 2015; 6:8081 [PubMed] Free Access to Full Article Related Publications
Unbiased dissection of T-cell receptor (TCR) repertoire diversity at the nucleotide level could provide important insights into human immunity. Here we show that TCR ligation-anchored-magnetically captured PCR (TCR-LA-MC PCR) identifies TCR α- and β-chain diversity without sequence-associated or quantitative restrictions in healthy and diseased conditions. TCR-LA-MC PCR identifies convergent recombination events, classifies different stages of cutaneous T-cell lymphoma in vivo and demonstrates TCR reactivation after in vitro cytomegalovirus stimulation. TCR-LA-MC PCR allows ultra-deep data access to both physiological TCR diversity and mechanisms influencing clonality in all clinical settings with restricted or distorted TCR repertoires.

Yew PY, Alachkar H, Yamaguchi R, et al.
Quantitative characterization of T-cell repertoire in allogeneic hematopoietic stem cell transplant recipients.
Bone Marrow Transplant. 2015; 50(9):1227-34 [PubMed] Free Access to Full Article Related Publications
Allogeneic hematopoietic stem cell transplantation (HSCT) is one of curative treatment options for patients with hematologic malignancies. Although GVHD mediated by the donor's T lymphocytes remains the most challenging toxicity of allo-HSCT, graft-versus-leukemia (GVL) effect targeting leukemic cells, has an important role in affecting the overall outcome of patients with AML. Here we comprehensively characterized the TCR repertoire in patients who underwent matched donor or haplo-cord HSCT using next-generation sequencing approach. Our study defines the functional kinetics of each TCRA and TCRB clone, and changes in T-cell diversity (with identification of CDR3 sequences) and the extent of clonal expansion of certain T-cells. Using this approach, our study demonstrates that higher percentage of cord-blood cells at 30 days after transplant was correlated with higher diversity of TCR repertoire, implicating the role of cord-chimerism in enhancing immune recovery. Importantly, we found that GVHD and relapse, exclusive of each other, were correlated with lower TCR repertoire diversity and expansion of certain T-cell clones. Our results highlight novel insights into the balance between GVHD and GVL effect, suggesting that higher diversity early after transplant possibly implies lower risks of both GVHD and relapse following the HSCT transplantation.

Sheng N, Li Z, Su W, et al.
A Case of Primary Cutaneous Aggressive Epidermotropic CD8+ Cytotoxic T-cell Lymphoma Misdiagnosed as Febrile Ulceronecrotic Mucha-Habermann Disease.
Acta Derm Venereol. 2016; 96(1):136-7 [PubMed] Related Publications

Shao H, Lin Y, Wang T, et al.
Identification of peptide-specific TCR genes by in vitro peptide stimulation and CDR3 length polymorphism analysis.
Cancer Lett. 2015; 363(1):83-91 [PubMed] Related Publications
Identification of TCR genes specific for tumor-associated antigens (TAAs) is necessary for TCR gene modification of T cells, which is applied in anti-tumor adoptive T cell therapy (ACT). The usual identification methods are based on isolating single peptide-responding T cells and cloning the TCR gene by in vitro expansion or by single-cell RT-PCR. However, the long and exacting in vitro culture period and demanding operational requirements restrict the application of these methods. Immunoscope is an effective tool that profiles a repertoire of TCRs and identifies significantly expanded clones through CDR3 length analysis. In this study, a survivin-derived mutant peptide optimized for HLA-A2 binding was selected to load DCs and activate T cells. The monoclonal expansion of TCRA and TCRB genes was separately identified by Immunoscope analysis and following sequence identification, the properly paired TCR genes were transferred into T cells. Peptide recognition and cytotoxicity assays indicated that TCR-modified PBMCs could respond to both the mutant and wild type peptides and lyse target cells. These results show that combining Immunoscope with in vitro peptide stimulation provides an alternative and superior method for identifying specific TCR genes, which represents a significant advance for the application of TCR gene-modified T cells.

Finalet Ferreiro J, Rouhigharabaei L, Urbankova H, et al.
Integrative genomic and transcriptomic analysis identified candidate genes implicated in the pathogenesis of hepatosplenic T-cell lymphoma.
PLoS One. 2014; 9(7):e102977 [PubMed] Free Access to Full Article Related Publications
Hepatosplenic T-cell lymphoma (HSTL) is an aggressive lymphoma cytogenetically characterized by isochromosome 7q [i(7)(q10)], of which the molecular consequences remain unknown. We report here results of an integrative genomic and transcriptomic (expression microarray and RNA-sequencing) study of six i(7)(q10)-positive HSTL cases, including HSTL-derived cell line (DERL-2), and three cases with ring 7 [r(7)], the recently identified rare variant aberration. Using high resolution array CGH, we profiled all cases and mapped the common deleted region (CDR) at 7p22.1p14.1 (34.88 Mb; 3506316-38406226 bp) and the common gained region (CGR) at 7q22.11q31.1 (38.77 Mb; 86259620-124892276 bp). Interestingly, CDR spans a smaller region of 13 Mb (86259620-99271246 bp) constantly amplified in cases with r(7). In addition, we found that TCRG (7p14.1) and TCRB (7q32) are involved in formation of r(7), which seems to be a byproduct of illegitimate somatic rearrangement of both loci. Further transcriptomic analysis has not identified any CDR-related candidate tumor suppressor gene. Instead, loss of 7p22.1p14.1 correlated with an enhanced expression of CHN2 (7p14.1) and the encoded β2-chimerin. Gain and amplification of 7q22.11q31.1 are associated with an increased expression of several genes postulated to be implicated in cancer, including RUNDC3B, PPP1R9A and ABCB1, a known multidrug resistance gene. RNA-sequencing did not identify any disease-defining mutation or gene fusion. Thus, chromosome 7 imbalances remain the only driver events detected in this tumor. We hypothesize that the Δ7p22.1p14.1-associated enhanced expression of CHN2/β2-chimerin leads to downmodulation of the NFAT pathway and a proliferative response, while upregulation of the CGR-related genes provides growth advantage for neoplastic δγT-cells and underlies their intrinsic chemoresistance. Finally, our study confirms the previously described gene expression profile of HSTL and identifies a set of 24 genes, including three located on chromosome 7 (CHN2, ABCB1 and PPP1R9A), distinguishing HSTL from other malignancies.

Ai X, Fu Q, Wang J, et al.
[Significance of BIOMED-2 standardized IG/TCR gene rearrangement detection in paraffin-embedded section in lymphoma diagnosis].
Zhonghua Xue Ye Xue Za Zhi. 2014; 35(6):495-8 [PubMed] Related Publications
OBJECTIVE: To explore the feasibility of detecting lymphoma with the application of BIOMED-2 standardized immunoglobulin/T cell receptor (IG/TCR) gene rearrangement system in formalin fixed paraffin-embedded (FFPE) tissue samples, and to discuss the relationship between the longest amplification fragment of extracted DNA and positive detection rate of different IGH V-J primers.
METHODS: DNA was extracted from 50 cases of FFPE tissue samples. Multiplex-PCR amplifications were performed and then the IG/TCR gene rearrangements were analyzed using BIOMED-2 standardized clonality analysis system.
RESULTS: (1)When the DNA concentration was diluted to 50-100 ng/μl from 100-500 ng/μl, the proportion of the longest amplification fragment (300-400 bp) of DNA was improved from 10.0% to 90.0% in 30 cases of diffuse large B cell lymphoma (DLBCL) wax roll samples (P<0.01). The positive rate of IGH+IGK was increased from 46.7% to 83.3%, the difference was statistically significant (P=0.006). The lengths of the longest amplification fragments of DNA were all longer than 300 bp in the paraffin section samples of DLBCL. The positive rate of IGH+IGK of these samples was 96.7%. The difference of the positive rate of IGH+IGK between the wax roll samples and the paraffin section samples had no statistical significance (P=0.195). (2)When the concentration of DNA was high, most of the longest amplification fragments of extracted DNA were 100 bp or 200 bp, and the detection rate of short fragment IGH FR3 was more stable than that of long fragment IGH FR1. (3)The clonality analysis of TCRG+TCRB in all 13 cases of peripheral T cell lymphoma samples showed positive results, while no positive IG/TCR clones were found in 7 cases of reactive lymphoid tissue hyperplasia in control group.
CONCLUSION: Dilution of DNA is the only method to improve not only the proportion of longest fragment amplification but also the detection rate of clonality. The detection rate of IGH FR3 would not be affected by the concentration of DNA. The application of BIOMED-2 standardized IG/TCR gene rearrangement system in FFPE tissue samples plays an important role in the lymphoma diagnosis.

Weng WK, Armstrong R, Arai S, et al.
Minimal residual disease monitoring with high-throughput sequencing of T cell receptors in cutaneous T cell lymphoma.
Sci Transl Med. 2013; 5(214):214ra171 [PubMed] Related Publications
Mycosis fungoides (MF) and the leukemic presentation Sézary syndrome (SS) are clonal T cell lymphomas arising from the skin and are considered noncurable with standard therapies. To develop a specific and sensitive monitoring tool, we tested the ability of high-throughput sequencing (HTS) of T cell receptors (TCRB) to monitor minimal residual disease (MRD) after allogeneic hematopoietic cell transplantation. Genomic DNA was extracted from peripheral blood mononuclear cells (PBMCs) or skin samples. The rearranged TCRβ loci were amplified using Vβ- and Jβ-specific primers, followed by HTS, to generate up to 1,000,000 reads spanning the CDR3 region of individual cells. Malignant clones were identified in diagnostic samples in all cases by a dominant CDR3 sequence. Before transplant, four patients had circulating Sézary cells by the routine flow cytometry, which was confirmed by TCRB HTS. Although the flow cytometry found no detectable Sézary cells, malignant clones were detected by TCRB HTS in all other six cases. Five patients achieved "molecular remission" in blood between +30 and +540 days after transplant. Four of these patients also achieved molecular clearance in skin after transplant. Experiments using blood samples spiked with purified Sézary cells demonstrated that TCRB HTS can detect Sézary cells at the level of 1 in 50,000 PBMCs, which is more sensitive than standard diagnostics. We have thus demonstrated the utility of TCRB HTS to assess MRD with increased sensitivity and specificity compared to other current methodologies, and to monitor response to therapy in this MF/SS patient population.

Gerlinger M, Quezada SA, Peggs KS, et al.
Ultra-deep T cell receptor sequencing reveals the complexity and intratumour heterogeneity of T cell clones in renal cell carcinomas.
J Pathol. 2013; 231(4):424-32 [PubMed] Free Access to Full Article Related Publications
The recognition of cancer cells by T cells can impact upon prognosis and be exploited for immunotherapeutic approaches. This recognition depends on the specific interaction between antigens displayed on the surface of cancer cells and the T cell receptor (TCR), which is generated by somatic rearrangements of TCR α- and β-chains (TCRb). Our aim was to assess whether ultra-deep sequencing of the rearranged TCRb in DNA extracted from unfractionated clear cell renal cell carcinoma (ccRCC) samples can provide insights into the clonality and heterogeneity of intratumoural T cells in ccRCCs, a tumour type that can display extensive genetic intratumour heterogeneity (ITH). For this purpose, DNA was extracted from two to four tumour regions from each of four primary ccRCCs and was analysed by ultra-deep TCR sequencing. In parallel, tumour infiltration by CD4, CD8 and Foxp3 regulatory T cells was evaluated by immunohistochemistry and correlated with TCR-sequencing data. A polyclonal T cell repertoire with 367-16 289 (median 2394) unique TCRb sequences was identified per tumour region. The frequencies of the 100 most abundant T cell clones/tumour were poorly correlated between most regions (Pearson correlation coefficient, -0.218 to 0.465). 3-93% of these T cell clones were not detectable across all regions. Thus, the clonal composition of T cell populations can be heterogeneous across different regions of the same ccRCC. T cell ITH was higher in tumours pretreated with an mTOR inhibitor, which could suggest that therapy can influence adaptive tumour immunity. These data show that ultra-deep TCR-sequencing technology can be applied directly to DNA extracted from unfractionated tumour samples, allowing novel insights into the clonality of T cell populations in cancers. These were polyclonal and displayed ITH in ccRCC. TCRb sequencing may shed light on mechanisms of cancer immunity and the efficacy of immunotherapy approaches.

Kobayashi E, Mizukoshi E, Kishi H, et al.
A new cloning and expression system yields and validates TCRs from blood lymphocytes of patients with cancer within 10 days.
Nat Med. 2013; 19(11):1542-6 [PubMed] Related Publications
Antigen-specific T cell therapy, or T cell receptor (TCR) gene therapy, is a promising immunotherapy for infectious diseases and cancers. However, a suitable rapid and direct screening system for antigen-specific TCRs is not available. Here, we report an efficient cloning and functional evaluation system to determine the antigen specificity of TCR cDNAs derived from single antigen-specific human T cells within 10 d. Using this system, we cloned and analyzed 380 Epstein-Barr virus-specific TCRs from ten healthy donors with latent Epstein-Barr virus infection and assessed the activity of cytotoxic T lymphocytes (CTLs) carrying these TCRs against antigenic peptide-bearing target cells. We also used this system to clone tumor antigen-specific TCRs from peptide-vaccinated patients with cancer. We obtained 210 tumor-associated antigen-specific TCRs and demonstrated the cytotoxic activity of CTLs carrying these TCRs against peptide-bearing cells. This system may provide a fast and powerful approach for TCR gene therapy for infectious diseases and cancers.

Emerson RO, Sherwood AM, Rieder MJ, et al.
High-throughput sequencing of T-cell receptors reveals a homogeneous repertoire of tumour-infiltrating lymphocytes in ovarian cancer.
J Pathol. 2013; 231(4):433-40 [PubMed] Free Access to Full Article Related Publications
The cellular adaptive immune system mounts a response to many solid tumours mediated by tumour-infiltrating T lymphocytes (TILs). Basic measurements of these TILs, including total count, show promise as prognostic markers for a variety of cancers, including ovarian and colorectal. In addition, recent therapeutic advances are thought to exploit this immune response to effectively fight melanoma, with promising studies showing efficacy in additional cancers. However, many of the basic properties of TILs are poorly understood, including specificity, clonality, and spatial heterogeneity of the T-cell response. We utilize deep sequencing of rearranged T-cell receptor beta (TCRB) genes to characterize the basic properties of TILs in ovarian carcinoma. Due to somatic rearrangement during T-cell development, the TCR beta chain sequence serves as a molecular tag for each T-cell clone. Using these sequence tags, we assess similarities and differences between infiltrating T cells in discretely sampled sections of large tumours and compare to T cells from peripheral blood. Within the limits of sensitivity of our assay, the TIL repertoires show strong similarity throughout each tumour and are distinct from the circulating T-cell repertoire. We conclude that the cellular adaptive immune response within ovarian carcinomas is spatially homogeneous and distinct from the T-cell compartment of peripheral blood.

Miyagawa F, Fukumoto T, Yurugi S, et al.
CD8+ primary cutaneous peripheral T-cell lymphoma in an 18-year-old woman.
J Dermatol. 2013; 40(7):571-2 [PubMed] Related Publications

Boone E, Verhaaf B, Langerak AW
PCR-based analysis of rearranged immunoglobulin or T-cell receptor genes by GeneScan analysis or heteroduplex analysis for clonality assessment in lymphoma diagnostics.
Methods Mol Biol. 2013; 971:65-91 [PubMed] Related Publications
The assessment of the presence of clonal lymphoproliferations via polymerase chain reaction (PCR)-based analysis of rearranged immunoglobulin (Ig) or T-cell receptor (TCR) genes is a valuable technique in the diagnosis of suspect lymphoproliferative disorders. Furthermore this technique is more and more used to evaluate dissemination of non-Hodgkin lymphoma and/or the presence of (minimal) residual disease. In this chapter we describe an integrated approach to assess clonality via analysis of Ig heavy chain (IGH), Ig kappa (IGK), TCR beta (TCRB), and TCR gamma (TCRG) gene rearrangements. The described PCR protocol is based on the standardized multiplex PCRs as developed by the European BIOMED-2 collaborative study (Concerted Action BMH4-CT98-3936). Furthermore it also includes the pre-analytical DNA isolation step from various tissues (formalin fixed paraffin-embedded tissue, fresh tissues, body fluids, peripheral blood and bone marrow), GeneScan analysis of labeled PCR products on a genetic analyzer, heteroduplex analysis of unlabeled PCR products, and post-analytical guidelines for the interpretation of the obtained "molecular morphology" patterns.

Wu D, Sherwood A, Fromm JR, et al.
High-throughput sequencing detects minimal residual disease in acute T lymphoblastic leukemia.
Sci Transl Med. 2012; 4(134):134ra63 [PubMed] Related Publications
High-throughput sequencing (HTS) of lymphoid receptor genes is an emerging technology that can comprehensively assess the diversity of the immune system. Here, we applied HTS to the diagnosis of T-lineage acute lymphoblastic leukemia/lymphoma. Using 43 paired patient samples, we then assessed minimal residual disease (MRD) at day 29 after treatment. The variable regions of TCRB and TCRG were sequenced using an Illumina HiSeq platform after performance of multiplexed polymerase chain reaction, which targeted all potential V-J rearrangement combinations. Pretreatment samples were used to define clonal T cell receptor (TCR) complementarity-determining region 3 (CDR3) sequences, and paired posttreatment samples were evaluated for MRD. Abnormal T lymphoblast identification by multiparametric flow cytometry was concurrently performed for comparison. We found that TCRB and TCRG HTS not only identified clonality at diagnosis in most cases (31 of 43 for TCRB and 27 of 43 for TCRG) but also detected subsequent MRD. As expected, HTS of TCRB and TCRG identified MRD that was not detected by flow cytometry in a subset of cases (25 of 35 HTS compared with 13 of 35, respectively), which highlights the potential of this technology to define lower detection thresholds for MRD that could affect clinical treatment decisions. Thus, next-generation sequencing of lymphoid receptor gene repertoire may improve clinical diagnosis and subsequent MRD monitoring of lymphoproliferative disorders.

Wu RQ, Qiao C, Tong Y, et al.
[Study of immunoglobulin and T-cell receptor gene rearrangements in patients with non-Hodgkin's lymphoma].
Zhonghua Xue Ye Xue Za Zhi. 2012; 33(1):10-5 [PubMed] Related Publications
OBJECTIVE: To investigate immunoglobulin (Ig) and T cell receptor (TCR) gene rearrangements in bone marrow or peripheral blood of patients with non-Hodgkin's lymphoma (NHL), and to explore the potential clinical significance.
METHODS: The Ig/TCR gene rearrangements in bone marrow or peripheral blood of 139 NHL patients were analyzed by using BIOMED-2 multiple primers system and Multiplex PCR assay.
RESULTS: Ig clonality was detected in 85.4% (70/82) of chronic lymphocytic leukemia (CLL), including 46.3% (38/82) IgH rearrangement, 62.2% (51/82) IgK rearrangement and 1.2% (1/82) IgL rearrangement, and in 39.4% (13/33) of other categories of B-lineage NHL (B-NHL), including 33.3% (11/33) IgH and 39.4% (13/33) IgK rearrangements. TCR clonality was detected in 50.0% (12/24) of all definite T-lineage NHL (T-NHL), including 8.3% (2/24) TCRB and 45.8% (11/24) TCRG, no TCRD was detected. The detection rate of gene rearrangements of NHL diversed in different clinical stages \[36.4% in early stage (Ann Arbor stage I and II) and 45.6% in late stage (III and IV)\] and in different degrees of malignancy (40.0% indolent NHL and 45.6% aggressive NHL), but no obvious statistical significance was obtained (P > 0.05). The detection rate of bone marrow invasions of NHL (except CLL) with examinations of bone marrow smear under the microscope was 12.3% (7/57), much lower than the clonality testing (43.9%, 25/57) (P < 0.05). Sensitivity test showed that the sensitivity of malignant clonality testing by multiplex PCR was 3.12% - 6.25%.
CONCLUSIONS: The detection rate of gene rearrangements diverses in different clinical stages and degrees of malignancy of NHL, but the correlation has not been proved in this research. The sensitivity of multiplex PCR-based clonality testing is enhanced with the combination of BIOMED-2 primers system. It is more sensitive than the morphological examinations of bone marrow smear in detecting bone marrow invasions, and may provide a powerful strategy in the routine diagnosis and assessment after treatment.

Onozawa M, Aplan PD
Illegitimate V(D)J recombination involving nonantigen receptor loci in lymphoid malignancy.
Genes Chromosomes Cancer. 2012; 51(6):525-35 [PubMed] Free Access to Full Article Related Publications
V(D)J recombination of antigen receptor loci (IGH, IGK, IGL, TCRA, TCRB, TCRG, and TCRD) is an essential mechanism that confers enormous diversity to the mammalian immune system. However, there are now at least six examples of intrachromosomal interstitial deletions caused by aberrant V(D)J recombination between nonantigen receptor loci; five of out these six are associated with lymphoid malignancy. The SIL-SCL fusion and deletions of CDKN2A, IKZF1, Notch1, and Bcl11b are all associated with lymphoid malignancy. These interstitial deletions seem to be species specific, as the deletions seen in mice are not seen in humans; the converse is true as well. Nucleotide sequence analysis of these rearrangements reveals the hallmarks of V(D)J recombination, including site specificity near cryptic heptamer signal sequences, exonucleolytic "nibbling" at the junction site, and nontemplated "N"-region nucleotide insertion at the junction site. Two of these interstitial deletions (murine Notch1 and Bcl11b deletions) have been detected, at low frequency, in tissues from healthy mice with no evidence of malignancy, similar to the finding of chromosomal translocations in the peripheral blood or tonsils of healthy individuals. The contention that these are mediated via V(D)J recombination is strengthened by in vivo assays using extrachromosomal substrates, and chromatin immunoprecipitation-sequence analysis which shows Rag2 binding at the sites of rearrangement. Although the efficiency of these "illegitimate" recombination events is several orders of magnitude less than that at bona fide antigen receptor loci, the consequence of such deletions, namely activation of proto-oncogenes or deletion of tumor suppressor genes, is devastating, and a major cause for lymphoid malignancy.

Tembhare P, Yuan CM, Morris JC, et al.
Flow cytometric immunophenotypic assessment of T-cell clonality by vβ repertoire analysis in fine-needle aspirates and cerebrospinal fluid.
Am J Clin Pathol. 2012; 137(2):220-6 [PubMed] Related Publications
Flow cytometric T-cell receptor V(β) repertoire analysis (TCR-V(β)-R) is a sensitive method to detect T-cell clonality; however, its implementation in low-cellularity specimens has not been established. We developed a strategy to use TCR-V(β)-R in cerebrospinal fluid (CSF) and fine-needle aspirate (FNA) specimens. Initially, full TCR-V(β)-R was evaluated in diagnostic/screening specimens from 8 patients with T-cell neoplasia to determine tumor-specific TCR-V(β) protein expression. Subsequently, an abbreviated, patient-specific TCR-V(β)-R evaluation was performed in 17 paucicellular specimens from the patients (8 CSF, 9 FNA) for staging and monitoring of minimal residual disease (MRD). A single cocktail containing 3 anti-V(β) antibodies (1 tumor-specific and 2 negative controls) in combination with other antibodies chosen to help gate on atypical T cells is highly sensitive and specific for detecting low-level neoplastic T-cell involvement in paucicellular specimens. This TCR-V(β)-R strategy is valuable in staging and evaluating MRD in patients with T-cell non-Hodgkin lymphoma.

Tong CR, Wang H, Lin YH, et al.
[The clinical and laboratory features of 9 cases with gammadeltaT cell lymphoma or leukemia].
Zhonghua Xue Ye Xue Za Zhi. 2011; 32(7):445-9 [PubMed] Related Publications
OBJECTIVE: To analyze the clinical and laboratory features of 9 cases of gammadeltaT cell lymphoma or leukemia.
METHODS: From 2007 to 2011, 9 patients with gammadeltaT-cell lymphoma/leukemia were diagnosed in our hospital. The immunophenotype of the abnormal cells were detected by flow cytometry, clonal gene rearrangement of IgH, TCRgamma, TCRdelta by PCR, chromosome karyotype analysis by G banding, acute leukemia gene and the DNA of type 1 - 8 human herpes virus by multiple nested PCR, The gammadeltaT cells were determined by T cell with TCR gammadelta chain, the malignant gammadelta T cells by the abnormal expression of T cell antigens and the precursor malignant gammadelta T cells by the expression of CD34, TDT, CD99, CD1 a or acute leukemia genes.
RESULTS: In the 9 patients with gammadeltaT cell lymphoma leukemia, significant malignant gammadeltaT cells infiltration of bone marrow were found in 8 with blast morphology. 5 were diagnosed as T-ALL/LBL (gammadeltaT type) and 4 HSgammadelta TCL. The clonal gene rearrangement of TCRgamma and/or TCRB were detected in 6/6 patients. Patients either did not achieve complete remission(CR) after induction therapy or relapsed quickly after CR. Only 4/5 patients remained continuous CR(CCR) at 2, 2, 3,12 months respectively, after allogeneic hematopoietic stem cell transplantation (allo-HSCT), the fifth T-ALL (gammadeltaT) relapsed 1 month after allo-HSCT.
CONCLUSIONS: The incidence of gammadelta T cell lymphoma or leukemia may be higher than reported, part of them were T-ALL/LBL with poor prognoses. FCM and clonal gene rearrangement of TCRgamma and/or TCRdelta are helpful to diagnosis. Allo-HSCT may be the only curative approach.

Yamazaki S, Fujioka Y, Nakamura F, et al.
Composite diffuse large B-cell lymphoma and CD20-positive peripheral T-cell lymphoma.
Pathol Int. 2011; 61(11):662-6 [PubMed] Related Publications
Composite lymphoma is defined as two or more distinct types of lymphoma in a single anatomical site. Among various combinations, composite B-cell and T-cell non-Hodgkin's lymphomas (CBTL) are very infrequent. Herein we describe a 66-year-old female with CBTL presenting with lymphadenopathy, multiple bone lesions and an epidural tumor. Light microscopic examination of a biopsied cervical node revealed a dual population of lymphoid cells: sheets of large cells admixed with medium-sized cells. The large cells expressed B-cell markers and showed immunoglobulin light chain restriction, consistent with diffuse large B-cell lymphoma (DLBCL). The medium-sized cells were positive for CD20 as well as T-cell markers. Because polymerase chain reaction amplification showed monoclonal rearrangement of the T-cell receptor β chain gene, this population was compatible with peripheral T-cell lymphoma not otherwise specified (PTCL-NOS). We therefore made a diagnosis of composite DLBCL and CD20-positive PTCL-NOS. Complete remission was achieved after six cycles of R-CHOP regimen (rituximab, doxorubicin, vincristine, cyclophosphamide and prednisolone). This is the first report of CD20-positive PTCL-NOS associated with composite lymphoma. Moreover, a literature review of composite DLBCL and PTCL-NOS indicates that this rare clinical entity may be featured by efficacy of systemic chemotherapy in spite of prevalent extranodal lesions.

Salgado R, Gallardo F, Servitje O, et al.
Absence of TCR loci chromosomal translocations in cutaneous T-cell lymphomas.
Cancer Genet. 2011; 204(7):405-9 [PubMed] Related Publications
Chromosomal aberrations involving T-cell receptor (TCR) gene loci have been described in several T-cell malignancies. In primary cutaneous T-cell lymphomas (CTCL), the frequency of these aberrations has not yet been well established. We analyzed TCR gene loci (TCRAD, TCRB, and TCRG) status in CTCLs by fluorescence in situ hybridization (FISH). Twenty-five patients with CTCLs were included in the study: 13 Sézary syndromes (SS), six tumoral stage mycosis fungoides (MFt), and six primary cutaneous anaplastic large cell lymphomas CD30(+) (cALCL-CD30(+)). FISH was performed with three break-apart probes flanking TCRAD (14q11), TCRB (7q34), and TCRG (7p14) loci in each case. TCR gene chromosomal rearrangements were not detected in any of the analyzed cases. Gains of TCRB and TCRG genes were observed in 23% (3 of 13) of SS and 50% (3 of 6) of MFt, reflecting the presence of trisomy and/or tetrasomy of chromosome 7 already detected by conventional cytogenetics and array comparative genetic hybridization techniques. TCR loci rearrangements are not frequent in CTCLs; however, we cannot exclude a pathogenic role in these malignancies.

Steininger A, Möbs M, Ullmann R, et al.
Genomic loss of the putative tumor suppressor gene E2A in human lymphoma.
J Exp Med. 2011; 208(8):1585-93 [PubMed] Free Access to Full Article Related Publications
The transcription factor E2A is essential for lymphocyte development. In this study, we describe a recurrent E2A gene deletion in at least 70% of patients with Sézary syndrome (SS), a subtype of T cell lymphoma. Loss of E2A results in enhanced proliferation and cell cycle progression via derepression of the protooncogene MYC and the cell cycle regulator CDK6. Furthermore, by examining the gene expression profile of SS cells after restoration of E2A expression, we identify several E2A-regulated genes that interfere with oncogenic signaling pathways, including the Ras pathway. Several of these genes are down-regulated or lost in primary SS tumor cells. These data demonstrate a tumor suppressor function of E2A in human lymphoid cells and could help to develop new treatment strategies for human lymphomas with altered E2A activity.

Ichikawa K, Noguchi M, Imai H, et al.
A case of T cell prolymphocytic leukemia involving blast transformation.
Int J Hematol. 2011; 93(5):667-72 [PubMed] Related Publications
We report a case of T cell prolymphocytic leukemia (T-PLL) involving blast transformation. At the initial diagnosis, most peripheral blood cells demonstrated proliferation of indolent T cell small cell variants, i.e., small to medium prolymphocytes with inconspicuous nucleoli and a normal karyotype. These cells were positive for surface CD4, CD5, and CD7, and cytoplasmic CD3, but negative for surface CD3 and CD8 and cytoplasmic terminal deoxynucleotidyl transferase (TdT). The T cell receptor (TCR) Cβ1 gene was rearranged in the cells. Large prolymphocytes with prominent nucleoli, irregular nuclei, and cytoplasmic vacuoles that exhibited chromosome 8 trisomy were observed about 1.5 years later. The CD4+CD8- single positive effector memory T cells transformed into surface CD4+CD8+ double positive precursor T cells. The clonal TCR gene rearrangement patterns of these cells were identical throughout the clinical course, suggesting clonal blast transformation. The CD4+CD8+ cells demonstrated increased chromosome 8 trisomy combined with complex chromosome abnormalities with t(14;14)(q11.2;q32) containing a 14q32 chromosome after transformation. T cell leukemia 1a (TCL1a) (14q32.1) may be implicated in this case. The TCL1a oncoprotein is expressed in approximately 70% of T-PLL cases. The disease gradually developed resistance to chemotherapy, and the patient died of the disease. It is known that indolent T-PLL can become aggressive. Therefore, similar transformations may occur in other aggressive T-PLL cases, particularly those involving trisomy 8 and TCL1a.

Mandava S, Sonar R, Ahmad F, et al.
Cytogenetic and molecular characterization of a hepatosplenic T-cell lymphoma: report of a novel chromosomal aberration.
Cancer Genet. 2011; 204(2):103-7 [PubMed] Related Publications
Hepatosplenic T-cell lymphomas (HSTCL) are rare cancers and comprise 5% of peripheral T-cell lymphomas. These well-characterized extranodal lymphomas have a disguised onset, secondary to intrasinusoidal infiltration of the spleen, liver, and bone marrow, with a rapidly progressive course that is poorly responsive to chemotherapy and often ensues in the setting of immune system suppression. We describe the clinical, immunophenotypic, cytogenetic, fluorescence in situ hybridization, and molecular analyses for T cell receptor gene rearrangement in a 21-year-old man diagnosed with HSTCL. Immunophenotypic analysis revealed negativity for CD5 as well as double negativity for CD4/CD8 mature T-cell immunophenotype, which suggested the diagnosis of hepatosplenic T-cell lymphoma. Molecular analysis confirmed a TCR gene rearrangement, thereby verifying the common T-cell origin of the present HSTCL case. Furthermore, cytogenetic analysis revealed a novel chromosomal rearrangement, t(7;15)(p22;q21). Metaphase fluorescence in situ hybridization analysis confirmed the translocation of a chromosomal segment from 15q21 to 7p22.

Li Y, Geng S, Du X, et al.
Restricted TRBV repertoire in CD4+ and CD8+ T-cell subsets from CML patients.
Hematology. 2011; 16(1):43-9 [PubMed] Related Publications
T-cell immunodeficiency is a common feature in cancer patients, which may relate to initiation and development of tumor. In expanding our previous observations in this area, we studied the repertoire of T-cell receptor beta variable region (TRBV) and T-cell proliferative history in CD4+ and CD8+ T cells from chronic myeloid leukemia (CML) patients. The expression and clonality analysis were performed by reverse transcription-polymerase chain reaction (RT-PCR) and GeneScan technique in peripheral blood mononuclear cells (PBMCs), CD4+ and CD8+ subsets of T cells. Nineteen CML cases in chronic phase were selected for this study and 17 healthy individuals served as controls. Marked restriction of TRBV repertoire was observed in both CD4+ and CD8+ T cells from CML. In most CML samples, clonally expanded T cells were identified in CD4+ and CD8+ T cells, predominantly in TRBV19 and TRBV21 (5/19) subfamilies. In conclusion, the restricted expression of TRBV subfamilies indicates the T-cell immunodeficiency in CML patients; however, clonally expanded T cells suggest a specific immune response to leukemia associated antigens.

Zuleger CL, Macklin MD, Bostwick BL, et al.
In vivo 6-thioguanine-resistant T cells from melanoma patients have public TCR and share TCR beta amino acid sequences with melanoma-reactive T cells.
J Immunol Methods. 2011; 365(1-2):76-86 [PubMed] Free Access to Full Article Related Publications
In vivo hypoxanthine-guanine phosphoribosyltransferase (HPRT)-deficient T cells (MT) from melanoma patients are enriched for T cells with in vivo clonal amplifications that traffic between blood and tumor tissues. Melanoma is thus a model cancer to test the hypothesis that in vivo MT from cancer patients can be used as immunological probes for immunogenic tumor antigens. MT were obtained by 6-thioguanine (TG) selection of lymphocytes from peripheral blood and tumor tissues, and wild-type T cells (WT) were obtained analogously without TG selection. cDNA sequences of the T cell receptor beta chains (TRB) were used as unambiguous biomarkers of in vivo clonality and as indicators of T cell specificity. Public TRB were identified in MT from the blood and tumor of different melanoma patients. Such public TRB were not found in normal control MT or WT. As an indicator of T cell specificity for melanoma, the >2600 MT and WT TRB, including the public TRB from melanoma patients, were compared to a literature-derived empirical database of >1270 TRB from melanoma-reactive T cells. Various degrees of similarity, ranging from 100% conservation to 3-amino acid motifs (3-mer), were found between both melanoma patient MT and WT TRBs and the empirical database. The frequency of 3-mer and 4-mer TRB matching to the empirical database was significantly higher in MT compared with WT in the tumor (p=0.0285 and p=0.006, respectively). In summary, in vivo MT from melanoma patients contain public TRB as well as T cells with specificity for characterized melanoma antigens. We conclude that in vivo MT merit study as novel probes for uncharacterized immunogenic antigens in melanoma and other malignancies.

Clark RA, Shackelton JB, Watanabe R, et al.
High-scatter T cells: a reliable biomarker for malignant T cells in cutaneous T-cell lymphoma.
Blood. 2011; 117(6):1966-76 [PubMed] Free Access to Full Article Related Publications
In early-stage cutaneous T-cell lymphoma (CTCL), malignant T cells are confined to skin and are difficult to isolate and discriminate from benign reactive cells. We found that T cells from CTCL skin lesions contained a population of large, high-scatter, activated skin homing T cells not observed in other inflammatory skin diseases. High-scatter T (T(HS)) cells were CD4(+) in CD4(+) mycosis fungoides (MF), CD8(+) in CD8(+) MF, and contained only clonal T cells in patients with identifiable malignant Vβ clones. T(HS) cells were present in the blood of patients with leukemic CTCL, absent in patients without blood involvement, and contained only clonal malignant T cells. The presence of clonal T(HS) cells correlated with skin disease in patients followed longitudinally. Clonal T(HS) cells underwent apoptosis in patients clearing on extracorporeal photopheresis but persisted in nonresponsive patients. Benign clonal T-cell proliferations mapped to the normal low-scatter T-cell population. Thus, the malignant T cells in both MF and leukemic CTCL can be conclusively identified by a unique scatter profile. This observation will allow selective study of malignant T cells, can be used to discriminate patients with MF from patients with other inflammatory skin diseases, to detect peripheral blood involvement, and to monitor responses to therapy.

Bialer G, Horovitz-Fried M, Ya'acobi S, et al.
Selected murine residues endow human TCR with enhanced tumor recognition.
J Immunol. 2010; 184(11):6232-41 [PubMed] Related Publications
TCR-gene transfer can mediate tumor regression in terminally ill melanoma patients. However, the formation of mix dimers between endogenous and transduced TCR chains may result in the surface dilution of the introduced TCR, which translates in poorer cellular avidity. Recently, we reported that murinization of human TCRs (i.e., the replacement of human C regions by murine ones) can improve TCR function. However, because xenogenic sequences may trigger immunogenicity, we sought to identify the essential murine residues that mediate this enhanced functional effect. We constructed murine/human chimeras of alpha- and beta-chains and assessed for their surface expression and function. We identified an evolutionary-unique lysine residue in Cbeta, central to murine TCR function. The mapping of Calpha revealed that a few short stretches of amino acids play a role in enhancing TCR function, one of the most important ones being the SDVP sequence. This information led us to design improved and minimally murinized human TCR C regions that mediate increased tumor recognition. This also enabled us to suggest a structural model that could explain the role of the aforementioned residues in promoting the preferential pairing and stability of murinized TCRs. Overall, these findings could have implications for the treatment of malignant diseases using TCR-gene transfer.

Kang YH, Son CY, Lee CH, Ryu CJ
Aberrant V(D)J cleavages in T cell receptor beta enhancer- and p53-deficient lymphoma cells.
Oncol Rep. 2010; 23(5):1463-8 [PubMed] Related Publications
Previously, we generated thymic lymphoma cell lines from EbetaR/Rp53-/- (EP) double mutant mice where the T cell receptor (TCR) beta enhancer (Ebeta) was deleted, and the p53 gene was inactivated. Here, we characterized the EP cell lines to study the roles of the Ebeta and p53 on TCRbeta rearrangements during lymphomagenesis. Recombination activation genes (RAGs) were expressed, while the TCRbeta chain was not expressed in the EP cell lines. Dbeta-Jbeta rearrangements were not detected at all, and Dbeta1 and Dbeta2 cleavages were also not detected in the EP cell lines. However, Jbeta cleavages suppressed in Ebeta mutant thymocytes were readily detected in the EP cell lines. The Jbeta cleavages appeared to be uncoupled, aberrant, RAG-dependent and Ebeta-independent and were not detected in a p53 or Ebeta single mutant background, suggesting that the Jbeta cleavages are selected in the Ebeta and p53 double mutant background. Sequence analysis showed that the cleavage occurred in the cryptic recombination signal sequences (RSSs) present throughout Jbeta gene segments. The results implicate that the uncoupled and aberrant V(D)J cleavages may contribute to double-strand break-mediated genome instability during lymphomagenesis in EP mice.

Conteduca G, Ferrera F, Pastorino L, et al.
The role of AIRE polymorphisms in melanoma.
Clin Immunol. 2010; 136(1):96-104 [PubMed] Related Publications
Polymorphisms of AIRE, a transcription factor that up-regulates intrathymic expression of tissue-specific antigens including melanoma-associated antigens (MAAs), may variably affect the selection of MAAs-specific thymocytes, generating T-cell repertoires protecting or predisposing individuals to melanoma. We found that AIRE single nucleotide polymorphisms (SNPs) rs1055311, rs1800520 and rs1800522 were significantly more frequent in healthy subjects than in melanoma patients, independently from sex, age and stages of melanoma. The presence of these SNPs was associated with increased frequency of two T-cell clonotypes specific for MAGE-1 linking their protective effect to selection/expansion of MAA-specific T cells. Interestingly, mRNA transcribed on the rs1800520 SNP showed increased free energy than the wild type suggesting that its reduced stability may be responsible for the different activity of the polymorphic AIRE molecule. This finding may contribute at identifying subjects with increased risk of developing melanoma or patients with melanoma that may take benefit from immunotherapy.

Zhang B, Beck AH, Taube JM, et al.
Combined use of PCR-based TCRG and TCRB clonality tests on paraffin-embedded skin tissue in the differential diagnosis of mycosis fungoides and inflammatory dermatoses.
J Mol Diagn. 2010; 12(3):320-7 [PubMed] Free Access to Full Article Related Publications
The distinction between mycosis fungoides (MF) and inflammatory dermatoses (ID) by clinicopathologic criteria can be challenging. There is limited information regarding the performance characteristics and utility of TCRG and TCRB clonality assays in diagnosis of MF and ID from paraffin-embedded tissue sections. In this study, PCR tests were performed with both TCRG and TCRB BIOMED-2 clonality methods followed by capillary electrophoresis and Genescan analysis using DNA samples from 35 MF and 96 ID patients with 69 and 133 paraffin-embedded specimens, respectively. Performance characteristics were determined for each test individually and in combination. TCRG and TCRB tests demonstrated identical sensitivity (64%) and specificity (84%) when analyzed as individual assays. The positive predictive value, negative predictive value, and change of posttest MF probability over a range of MF pretest probabilities were obtained. These data were used to construct an algorithm for sequential use of TCRG and TCRB. As single tests, commercially available BIOMED-2 PCR-based TCRG and TCRB clonality tests on paraffin-embedded tissue have no significant difference in terms of sensitivity and specificity. Combined use of the two tests in patients with intermediate pretest probabilities as proposed in the algorithm could improve test utility.

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