Gene Summary

Gene:CD3D; CD3d molecule, delta (CD3-TCR complex)
Aliases: T3D, IMD19, CD3-DELTA
Summary:The protein encoded by this gene is part of the T-cell receptor/CD3 complex (TCR/CD3 complex) and is involved in T-cell development and signal transduction. The encoded membrane protein represents the delta subunit of the CD3 complex, and along with four other CD3 subunits, binds either TCR alpha/beta or TCR gamma/delta to form the TCR/CD3 complex on the surface of T-cells. Defects in this gene are a cause of severe combined immunodeficiency autosomal recessive T-cell-negative/B-cell-positive/NK-cell-positive (SCIDBNK). Two transcript variants encoding different isoforms have been found for this gene. Other variants may also exist, but the full-length natures of their transcripts has yet to be defined. [provided by RefSeq, Feb 2009]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:T-cell surface glycoprotein CD3 delta chain
Source:NCBIAccessed: 27 February, 2015


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 27 February 2015 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 27 February, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

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: CD3D (cancer-related)

Asghari Alashti F, Minuchehr Z
MiRNAs which target CD3 subunits could be potential biomarkers for cancers.
PLoS One. 2013; 8(11):e78790 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: T-cells play an important role in the immune response and are activated in response to the presentation of antigens bound to major histocompatibility complex (MHC) molecules participating with the T-cell receptor (TCR). T-cell receptor complexes also contain four CD3 (cluster of differentiation 3) subunits. The TCR-CD3 complex is vital for T-cell development and plays an important role in intervening cell recognition events. Since microRNAs (miRNAs) are highly stable in blood serum, some of which may target CD3 molecules, they could serve as good biomarkers for early cancer detection. The aim of this study was to see whether there is a relationship between cancers and the amount of miRNAs -targeted CD3 molecules.
METHODS: Bioinformatics tools were used in order to predict the miRNA targets for these genes. Subsequently, these highly conserved miRNAs were evaluated to see if they are implicated in various kinds of cancers. Consequently, human disease databases were used. According to the latest research, this study attempted to investigate the possible down- or upregulation of miRNAs cancer patients.
RESULTS: We identified miRNAs which target genes producing CD3 subunit molecules. The most conserved miRNAs were identified for the CD3G gene, while CD247 and CD3EAP genes had the least number and there were no conserved miRNA associated with the CD3D gene. Some of these miRNAs were found to be responsible for different cancers, following a certain pattern.
CONCLUSIONS: It is highly likely that miRNAs affect the CD3 molecules, impairing the immune system, recognizing and destroying cancer tumor; hence, they can be used as suitable biomarkers in distinguishing cancer in the very early stages of its development.

van den Hengel SK, Balvers RK, Dautzenberg IJ, et al.
Heterogeneous reovirus susceptibility in human glioblastoma stem-like cell cultures.
Cancer Gene Ther. 2013; 20(9):507-13 [PubMed] Related Publications
Glioblastoma (GB) is a devastating disease for which new treatment modalities are needed. Efficacious therapy requires the removal of stem-cell like cells, these cells drive tumor progression because of their ability to self-renew and differentiate. In glioblastoma, the GB stem-like cells (GSC) form a small population of tumor cells and possess high resistance to chemo and radiation therapies. To assess the sensitivity of GSC to reovirus-mediated cytolysis, a panel of GSC cultures was exposed to wild-type reovirus Type 3 Dearing (T3D) and its junction adhesion molecule-A (JAM-A)-independent mutant, jin-1. Several parameters were evaluated, including the fraction of cells expressing the JAM-A reovirus receptor, the fraction of cells synthesizing reovirus proteins, the number of infectious reovirus particles required to reduce cell viability, the amount of infectious progeny reovirus produced and the capacity of the reoviruses to infect the GSC in 3-dimensional (3D) tumor cell spheroids. Our data demonstrate a marked heterogeneity in the susceptibility of the cultures to reovirus-induced cytolysis. While in monolayer cultures the jin-1 reovirus was generally more cytolytic than the wild-type reovirus T3D, in the 3D GSC spheroids, these viruses were equally effective. Despite the variation in reovirus sensitivity between the different GSC cultures, our data support the use of reovirus as an oncolytic agent. It remains to be established whether the variation in the reovirus sensitivity correlates with a patient's response to reovirus therapy. Moreover, our data show that the expression of the JAM-A receptor is not a major determinant of reovirus sensitivity in 3D GSC cultures.

Dai Y, Tang Y, He F, et al.
Screening and functional analysis of differentially expressed genes in EBV-transformed lymphoblasts.
Virol J. 2012; 9:77 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Epstain-Barr virus (EBV) can transform human B lymphocytes making them immortalized and inducing tumorigenic ability in vitro, but the molecular mechanisms remain unclear. The aim of the present study is to detect and analyze differentially expressed genes in two types of host cells, normal human lymphocytes and coupled EBV-transformed lymphoblasts in vitro using gene chips, and to screen the key regulatory genes of lymphocyte transformation induced by EB virus.
METHODS: Fresh peripheral blood samples from seven healthy donors were collected. EBV was used to transform lymphocytes in vitro. Total RNA was extracted from 7 cases of the normal lymphocytes and transformed lymphoblasts respectively, marked with dihydroxyfluorane after reverse transcription, then hybridized with 4 × 44 K Agilent human whole genome microarray. LIMMA, String, Cytoscape and other softwares were used to screen and analyze differentially expressed genes. Real-time PCR was applied to verify the result of gene expression microarrays.
RESULTS: There were 1745 differentially expressed genes that had been screened, including 917 up-regulated genes and 828 down-regulated genes. According to the results of Generank, String and Cytoscape analyses, 38 genes may be key controlled genes related to EBV-transformed lymphocytes, including 22 up-regulated genes(PLK1, E2F1, AURKB, CDK2, PLCG2, CD80, PIK3R3, CDC20, CDC6, AURKA, CENPA, BUB1B, NUP37, MAD2L1, BIRC5, CDC25A, CCNB1, RPA3, HJURP, KIF2C, CDK1, CDCA8) and 16 down-regulated genes(FYN, CD3D, CD4, CD3G, ZAP70, FOS, HCK, CD247, PRKCQ, ITK, LCP2, CXCL1, CD8A, ITGB5, VAV3, CXCR4), which primarily control biological processes such as cell cycle, mitosis, cytokine-cytokine pathway, immunity response and so on.
CONCLUSIONS: Human lymphocyte transformation induced by EB virus is a complicated process, involving multiple-genes and -pathways in virus-host interactions. Global gene expression profile analysis showed that EBV may transform human B lymphocytes by promoting cell cycle and mitosis, inhibiting cell apoptosis, hindering host immune function and secretion of cytokines.

West NR, Milne K, Truong PT, et al.
Tumor-infiltrating lymphocytes predict response to anthracycline-based chemotherapy in estrogen receptor-negative breast cancer.
Breast Cancer Res. 2011; 13(6):R126 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Infiltration of breast tumors by tumor-infiltrating lymphocytes (TIL) has been associated with sensitivity to anthracycline-based chemotherapy. However, it is unclear whether this is true within the estrogen receptor-alpha (ER)-negative subset of breast tumors that frequently manifest high TIL levels.
METHODS: The association of TIL with short-term and long-term clinical response to anthracycline-based therapy was assessed in two independent ER-negative breast cancer cohorts in which patients were categorized as TIL-high or TIL-low. We defined an eight-gene lymphocyte mRNA expression signature (including CD19, CD3D, CD48, GZMB, LCK, MS4A1, PRF1, and SELL) and used unsupervised hierarchical clustering to examine the association between TIL and short-term response to neoadjuvant chemotherapy in a previously published cohort of ER-negative tumors (n = 113). We also examined the association between TIL and long-term chemotherapeutic efficacy in a second cohort of ER-negative tumors (n = 255) with longer than 6 years of median follow-up by using tissue microarrays and immunohistochemistry (IHC) for detection of CD3, CD8, CD4, CD20, and TIA-1.
RESULTS: In patients with ER-negative tumors treated with neoadjuvant anthracycline-based chemotherapy, pathologic complete responses (pCRs) were achieved by 23 (74%) of 31 TIL-high patients and 25 (31%) of 80 TIL-low patients (odds ratio (OR), 6.33; 95% confidence interval (CI), 2.49 to 16.08; P < 0.0001). Multivariate logistic regression with standard clinicopathologic features demonstrated that only tumor size (P = 0.037) and TIL status (P = 0.001) were independent predictors of anthracycline response. In the second cohort, adjuvant anthracycline-based therapy was associated with increased disease-free survival (DFS) only in patients with high levels of intraepithelial CD3+ TIL (P = 0.0023). In contrast, outcomes after CMF treatment (cyclophosphamide, methotrexate, and fluorouracil) showed no association with CD3 status. In both cohorts, cytotoxic T-cells were the primary TIL subtype associated with anthracycline sensitivity. Finally, TIL significantly predicted anthracycline sensitivity for both the Her2-positive and triple-negative tumor phenotypes.
CONCLUSIONS: ER-negative breast cancers with high levels of TIL have heightened sensitivity to anthracycline-based chemotherapy, as assessed by the immediate response to neoadjuvant therapy and long-term outcome following adjuvant therapy. Investigations of TIL-based predictive tests to identify patients likely to benefit from anthracycline-based treatments are warranted.

Denkert C, Loibl S, Noske A, et al.
Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer.
J Clin Oncol. 2010; 28(1):105-13 [PubMed] Related Publications
PURPOSE Preclinical data suggest a contribution of the immune system to chemotherapy response. In this study, we investigated the prespecified hypothesis that the presence of a lymphocytic infiltrate in cancer tissue predicts the response to neoadjuvant chemotherapy. METHODS We investigated intratumoral and stromal lymphocytes in a total of 1,058 pretherapeutic breast cancer core biopsies from two neoadjuvant anthracycline/taxane-based studies (GeparDuo, n = 218, training cohort; and GeparTrio, n = 840, validation cohort). Molecular parameters of lymphocyte recruitment and activation were evaluated by kinetic polymerase chain reaction in 134 formalin-fixed, paraffin-embedded tumor samples. Results In a multivariate regression analysis including all known predictive clinicopathologic factors, the percentage of intratumoral lymphocytes was a significant independent parameter for pathologic complete response (pCR) in both cohorts (training cohort: P = .012; validation cohort: P = .001). Lymphocyte-predominant breast cancer responded, with pCR rates of 42% (training cohort) and 40% (validation cohort). In contrast, those tumors without any infiltrating lymphocytes had pCR rates of 3% (training cohort) and 7% (validation cohort). The expression of inflammatory marker genes and proteins was linked to the histopathologic infiltrate, and logistic regression showed a significant association of the T-cell-related markers CD3D and CXCL9 with pCR. CONCLUSION The presence of tumor-associated lymphocytes in breast cancer is a new independent predictor of response to anthracycline/taxane neoadjuvant chemotherapy and provides useful information for oncologists to identify a subgroup of patients with a high benefit from this type of chemotherapy.

Van Den Wollenberg DJ, Van Den Hengel SK, Dautzenberg IJ, et al.
Modification of mammalian reoviruses for use as oncolytic agents.
Expert Opin Biol Ther. 2009; 9(12):1509-20 [PubMed] Related Publications
The Reoviridae are a family of viruses with a non-enveloped icosahedral capsid and a segmented double-stranded RNA genome. Prototypes of the mammalian Orthoreoviruses have been isolated from human respiratory and enteric tracts and are not associated with human disease. One of these, human reovirus type 3 Dearing (T3D), usually serves as a model for the family. In the last decade the mammalian Orthoreoviruses, especially T3D, have been evaluated as oncolytic agents in experimental cancer therapy. This is based on the observation that reoviruses induce cell death and apoptosis in tumor cells, but not in healthy non-transformed cells. Several clinical trials have been initiated in Canada, the USA, and the UK, to study the feasibility and safety of this approach. Due to the segmented structure of their double-stranded RNA genomes genetic modification of Reoviridae has been notoriously difficult. Several techniques have been described recently that facilitate the genetic modification of reovirus genomes. The basis for reverse genetics of reovirus is the discovery in 1990 that reovirus RNA is infectious. Subsequently, it took ten years before a foreign gene was introduced into the reovirus genome. Here we review the methods for reovirus modification and their use for generating new reovirus-derived oncolytic agents.

Bogunovic D, O'Neill DW, Belitskaya-Levy I, et al.
Immune profile and mitotic index of metastatic melanoma lesions enhance clinical staging in predicting patient survival.
Proc Natl Acad Sci U S A. 2009; 106(48):20429-34 [PubMed] Free Access to Full Article Related Publications
Although remission rates for metastatic melanoma are generally very poor, some patients can survive for prolonged periods following metastasis. We used gene expression profiling, mitotic index (MI), and quantification of tumor infiltrating leukocytes (TILs) and CD3+ cells in metastatic lesions to search for a molecular basis for this observation and to develop improved methods for predicting patient survival. We identified a group of 266 genes associated with postrecurrence survival. Genes positively associated with survival were predominantly immune response related (e.g., ICOS, CD3d, ZAP70, TRAT1, TARP, GZMK, LCK, CD2, CXCL13, CCL19, CCR7, VCAM1) while genes negatively associated with survival were cell proliferation related (e.g., PDE4D, CDK2, GREF1, NUSAP1, SPC24). Furthermore, any of the 4 parameters (prevalidated gene expression signature, TILs, CD3, and in particular MI) improved the ability of Tumor, Node, Metastasis (TNM) staging to predict postrecurrence survival; MI was the most significant contributor (HR = 2.13, P = 0.0008). An immune response gene expression signature and presence of TILs and CD3+ cells signify immune surveillance as a mechanism for prolonged survival in these patients and indicate improved patient subcategorization beyond current TNM staging.

van den Wollenberg DJ, van den Hengel SK, Dautzenberg IJ, et al.
A strategy for genetic modification of the spike-encoding segment of human reovirus T3D for reovirus targeting.
Gene Ther. 2008; 15(24):1567-78 [PubMed] Related Publications
Human Orthoreovirus Type 3 Dearing is not pathogenic to humans and has been evaluated clinically as an oncolytic agent. Its transduction efficiency and the tumor cell selectivity may be enhanced by incorporating ligands for alternative receptors. However, the genetic modification of reoviruses has been difficult, and genetic targeting of reoviruses has not been reported so far. Here we describe a technique for generating genetically targeted reoviruses. The propagation of wild-type reoviruses on cells expressing a modified sigma 1-encoding segment embedded in a conventional RNA polymerase II transcript leads to substitution of the wild-type genome segment by the modified version. This technique was used for generating reoviruses that are genetically targeted to an artificial receptor expressed on U118MG cells. These cells lack the junction adhesion molecule-1 and therefore resist infection by wild-type reoviruses. The targeted reoviruses were engineered to carry the ligand for this receptor at the C terminus of the sigma 1 spike protein. This demonstrates that the C terminus of the sigma 1 protein is a suitable locale for the insertion of oligopeptide ligands and that targeting of reoviruses is feasible. The genetically targeted viruses can be propagated using the modified U118MG cells as helper cells. This technique may be applicable for the improvement of human reoviruses as oncolytic agents.

Linderoth J, Edén P, Ehinger M, et al.
Genes associated with the tumour microenvironment are differentially expressed in cured versus primary chemotherapy-refractory diffuse large B-cell lymphoma.
Br J Haematol. 2008; 141(4):423-32 [PubMed] Related Publications
In order to identify genes associated with primary chemotherapy-resistance, gene expression profiles (GEP) in tumour tissue from 37 patients with de novo diffuse large B-cell lymphoma (DLBCL), stage II-IV, either in continuous complete remission (n = 24) or with progressive disease during primary treatment (n = 13), were examined using spotted 55K oligonucleotide arrays. Immunohistochemistry was used for confirmation at the protein level. The top 86 genes that best discriminated between the two cohorts were chosen for further analysis. Only seven of 86 genes were overexpressed in the refractory cohort, e.g. RABGGTB and POLE, both potential targets for drug intervention. Seventy-nine of 86 genes were overexpressed in the cured cohort and mainly coded for proteins expressed in the tumour microenvironment, many of them involved in proteolytic activity and remodelling of extra cellular matrix. Furthermore, major histocompatibility complex class I molecules, CD3D and ICAM1 were overexpressed, indicating an enhanced immunological reaction. Immunohistochemistry confirmed the GEP results. The frequency of tumour infiltrating lymphocytes, macrophages, and reactive cells expressing ICAM-1, lysozyme, cathepsin D, urokinase plasminogen activator receptor, signal transducer and activator of transcription 1, and galectin-3 was higher in the cured cohort. These findings indicate that a reactive microenvironment has an impact on the outcome of chemotherapy in DLBCL.

van Houdt WJ, Smakman N, van den Wollenberg DJ, et al.
Transient infection of freshly isolated human colorectal tumor cells by reovirus T3D intermediate subviral particles.
Cancer Gene Ther. 2008; 15(5):284-92 [PubMed] Related Publications
Reovirus T3D preferentially kills tumor cells expressing Ras oncogenes and has shown great promise as an anticancer agent in various preclinical tumor models. Here, we investigated whether reovirus can infect and kill tumor cell cultures and tissue fragments isolated from resected human colorectal tumors, and whether this was affected by the presence of endogenous oncogenic KRAS. Tissue fragments and single-cell populations isolated from human colorectal tumor biopsies were infected with reovirus virions or with intermediate subviral particles (ISVPs). Reovirus virions were capable of infecting neither single-cell tumor cell populations nor small fragments of intact viable tumor tissue. However, infection of tumor cells with ISVPs resulted in transient viral protein synthesis, irrespective of the presence of oncogenic KRAS, but this did not lead to the production of infectious virus particles, and tumor cell viability was largely unaffected. ISVPs failed to infect intact tissue fragments. Thermolysin treatment of tumor tissue liberated single cells from the tissue and allowed infection with ISVPs, but this did not result in the production of infectious virus particles. Immunohistochemistry on tissue microarrays showed that junction adhesion molecule 1, the major cellular reovirus receptor, was improperly localized in the cytoplasm of colorectal tumor cells and was expressed at very low levels in liver metastases. This may contribute to the observed resistance of tumor cells to reovirus T3D virions. We conclude that infection of human colorectal tumor cells by reovirus T3D requires processing of virions to ISVPs, but that oncolysis is prevented by a tumor cell response that aborts viral protein synthesis and the generation of infectious viral particles, irrespective of KRAS mutation status.

van Schothorst EM, Beekman M, Torremans P, et al.
Paragangliomas of the head and neck region show complete loss of heterozygosity at 11q22-q23 in chief cells and the flow-sorted DNA aneuploid fraction.
Hum Pathol. 1998; 29(10):1045-9 [PubMed] Related Publications
Nonchromaffin paragangliomas of the head and neck region, also known as glomus tumors, are usually benign neoplasms consisting of clusters of chief cells surrounded by sustentacular cells arranged in so-called 'Zellballen.' Most of the patients have a familial background. In a previous study, examining all chromosome arms, we found loss of heterozygosity (LOH) predominantly at the chromosome 11q22-q23 region, where the disease causing gene PGL1 has been located by linkage analysis. However, all tumors showed only partial loss of allele signal intensities, and it was not clear whether this represented allelic imbalance or cellular heterogeneity. In the current study, we have performed LOH analysis for the 11q22-q23 region on DNA-aneuploid tumor cells, enriched by flow sorting, and on purified chief cell fractions obtained by single-cell microdissection. Complete LOH was found for two markers (D11S560 and CD3D) in the flow-sorted aneuploid fractions, whereas no LOH was found in the diploid fractions of three tumors. The microdissected chief cells from two of these tumors also showed complete LOH for both markers, indicating that the chief cells are clonal proliferated tumor cells. These results indicate that the PGL1 gene is likely to be a tumor suppressor gene, which is inactivated according to the two-hit model of Knudson. Furthermore, it shows that chief cells are a major if not the sole neoplastic component of paragangliomas.

Baysal BE, Farr JE, Rubinstein WS, et al.
Fine mapping of an imprinted gene for familial nonchromaffin paragangliomas, on chromosome 11q23.
Am J Hum Genet. 1997; 60(1):121-32 [PubMed] Free Access to Full Article Related Publications
Hereditary nonchromaffin paragangliomas (PGL; glomus tumors; MIM 168000) are mostly benign, slow-growing tumors of the head and neck region, inherited from carrier fathers in an autosomal dominant fashion subject to genomic imprinting. Genetic linkage analysis in two large, unrelated Dutch families assigned PGL loci to two regions of chromosome 11, at 11q23 (PGL1) and 11q13.1 (PGL2). We ascertained a total of 11 North American PGL families and confirmed maternal imprinting (inactivation). In three of six families, linkage analysis provided evidence of linkage to the PGL1 locus at 11q23. Recombinants narrowed the critical region to an approximately 4.5-Mb interval flanked by markers D11S1647 and D11S622. Partial allelic loss of strictly maternal origin was detected in 5 of 19 tumors. The greatest degree of imbalance was detected at 11q23, distal to D11S1327 and proximal to CD3D. Age at onset of symptoms was significantly different between fathers and children (Wilcoxon rank-sum test, P < .002). Affected children had an earlier age at onset of symptoms in 39 of 57 father-child pairs (chi2 = 7.74, P < .006). However, a more conservative comparison of the number of pairs in which a child had > or = 5 years earlier age at onset (n = 33) vis-a-vis that of complementary pairs (n = 24) revealed no significant difference (chi2 = 1.42, P > .2). Whether these data represent genetic anticipation or ascertainment bias can be addressed only by analysis of a larger number of father-child pairs.

van Schothorst EM, Jansen JC, Bardoel AF, et al.
Confinement of PGL, an imprinted gene causing hereditary paragangliomas, to a 2-cM interval on 11q22-q23 and exclusion of DRD2 and NCAM as candidate genes.
Eur J Hum Genet. 1996; 4(5):267-73 [PubMed] Related Publications
Paragangliomas of the head and neck region, also known as glomus tumours, are mostly benign tumours of neuro-ectodermal origin. We mapped the familial form by linkage analysis in 6 families to chromosome region 11q22-q23, between the markers STMY and CD3D which currently span a 16-cM interval. Here, we performed detailed haplotype analysis of this region in a single Dutch multibranch 7-generation family. A region of 2 cM between the markers D11S938/D11S4122 and D11S1885 was shared between all patients of whom disease haplotypes could be reconstructed. In support of this localization, a recombination observed in a small French family with 2 affected nieces places the PGL gene proximal to marker D11S908, genetically coincident with D11S1885.

Rasio D, Negrini M, Manenti G, et al.
Loss of heterozygosity at chromosome 11q in lung adenocarcinoma: identification of three independent regions.
Cancer Res. 1995; 55(18):3988-91 [PubMed] Related Publications
We examined the pattern of allelic loss in 76 adenocarcinomas of the lung using 14 highly informative microsatellite markers on the long arm of chromosome 11. Loss of heterozygosity was found in 48 of 76 tumors (63%). Three distinct regions of deletion were identified. The first region, the most centromeric, lies between markers D11S940 and CD3D: the second, delimited by markers D11S924 and D11S925, is estimated to be 4 Mb in length, and has never been previously described; a third, more telomeric region, the length of which is also estimated to be in the range of 4 Mb, is bracketed by loci D11S1345 and D11S1328. These findings suggest the presence of at least three tumor suppressor genes on the long arm of chromosome 11, and confirm the relevance of 11q22-24, a region frequently deleted in carcinomas of the breast, ovary, uterine, cervix, colon, and malignant melanoma in the pathogenesis of solid tumors. The characterization of minimal regions of loss could provide the basis for the identification and cloning of the critical genes.

Rowe T, Dezzutti C, Guenthner PC, et al.
Characterization of a HTLV-I-infected cell line derived from a patient with adult T-cell leukemia with stable co-expression of CD4 and CD8.
Leuk Res. 1995; 19(9):621-8 [PubMed] Related Publications
A long-term T-cell line, termed SP+, was developed from a human T-cell leukemia virus type I (HTLV-I)-infected patient with adult T-cell leukemia that is dependent on exogenous IL-2 for growth. The SP+ expresses a full complimentation of HTLV-I-specific viral proteins, and contains replication competent viral particles. Restriction enzyme digestion followed by Southern blot analysis demonstrated the presence of a single integrated proviral copy and limiting dilution analysis confirmed the clonality of the cell line. Interestingly, phenotypically, the SP+ cell line is CD2+, CD3+ and coexpresses CD4 and CD8, yet lacks TCR alpha beta and TCR tau delta expression. Further ontogenetic characterization of the SP+ cell line demonstrated the lack of thymic T-cell precursor markers, including absence of cell surface expression of CD1, intracellular thymic terminal deoxynucleotidyl transferase (TdT) enzyme, as well as message expression for V(D)J recombinase activating gene-1 (RAG-1). Furthermore, the SP+ cell did express the message for the CD3 delta chain. Taken together, these data suggest that the SP+ cell line resulted from HTLV-I infection of a mature CD4+/CDB+ lymphocyte. This cell line can be potentially useful as a model, both for regulation of cellular functions by HTLV-I and for immunologic functions of mature dual CD4/CD8 positive T-cells.

Lüscher U, Filgueira L, Juretic A, et al.
The pattern of cytokine gene expression in freshly excised human metastatic melanoma suggests a state of reversible anergy of tumor-infiltrating lymphocytes.
Int J Cancer. 1994; 57(4):612-9 [PubMed] Related Publications
Expression of an extended panel of cytokine genes was investigated by reverse polymerase chain reaction (PCR) in 10 freshly excised melanoma metastases infiltrated by lymphocytes (TIL). cDNA encoding for CD3-delta and tyrosinase could be amplified in all samples, confirming the presence of T lymphocytes and melanoma cells. Cytokine genes possibly transcribed by both cell types, such as GM-CSF, IL-6 and IL-10 could be amplified from 5, 2 and 2 samples respectively. In contrast, IL-1 beta and TNF-alpha mRNA were never detectable, IL-1 alpha, IL-3 and IL-7 mRNA could be observed only in one case each. Transcripts encoding for TGF-beta 1 were observed in 8 samples, while TGF-beta 2 and 3 mRNA were detectable in only 2 specimens. mRNA encoding for cytokine genes typically transcribed by antigen-stimulated T lymphocytes, such as IL-2, IL-4 and IFN-gamma were rarely or never detectable (none, none and 1 of the samples respectively). In one case, where no cytokine gene transcription was detectable at the time of surgery, we addressed the question of the antigenicity of the tumor and of the functional competence of TIL. A primary tumor cell line was generated and cultured TIL were induced to transcribe IL-2 and IFN-gamma genes by incubation with the autologous irradiated tumor cell line, but not with autologous EBV-transformed cells. In these conditions, tumor-specific cytotoxic T lymphocytes (CTL) could be generated only after 3 weekly re-stimulations. In contrast, if autologous irradiated EBV-transformed cells were added to the cultures, specific CTL could be detected after one single tumor stimulation. Thus, signs of active responsiveness in terms of lymphokine gene mRNA are seldom detectable in melanoma metastases. Tumor-specific responses, however, including IL-2 and IFN-gamma gene expression and generation of CTL can be produced in vitro from specimens in which no cytokine gene mRNA is detectable ex vivo.

Yoneda N, Tatsumi E, Teshigawara K, et al.
Lineage determination of CD7+ CD5- CD2- and CD7+ CD5+ CD2- lymphoblasts: studies on phenotype, genotype, and gene expression of myeloperoxidase, CD3 epsilon, and CD3 delta.
Am J Hematol. 1994; 45(4):310-20 [PubMed] Related Publications
The gene expression of myeloperoxidase (MPO), CD3 epsilon, and CD3 delta molecules, the gene rearrangement of T-cell receptor (TCR) delta, gamma, and beta and immunoglobulin heavy (IgH) chain, and the expression of cell-surface antigens were investigated in seven cases of CD7+ CD5- CD2- and four cases of CD7+ CD5+ CD2- acute lymphoblastic leukemia or lymphoblastic lymphoma (ALL/LBL) blasts, which were negative for cytochemical myeloperoxidase (cyMPO). More mature T-lineage blasts were also investigated in a comparative manner. In conclusion, the CD7+ CD5- CD2- blasts included four categories: undifferentiated blasts without lineage commitment, T-lineage blasts, T-/myeloid lineage blasts, and cyMPO-negative myeloblasts. The CD7+ CD5+ CD2- blasts included two categories; T-lineage and T-/myeloid lineage blasts. The 11 cases were of the germ-line gene (G) for TCR beta and IgH. Four cases were G for TCR delta and TCR gamma. The others were of the monoclonally rearranged gene (R) for TCR delta and G for TCR gamma or R for both TCR delta and TCR gamma. The expression or in vitro induction of CD13 and/or CD33 antigens correlated with the immaturity of these neoplastic T cells, since it was observed in all 11 CD7+ CD5- CD2- and CD7+ CD5+ CD2-, and some CD7+ CD5+ CD2+ (CD3- CD4- CD8-) cases, but not in CD3 +/- CD4+ CD8+ or CD3+ CD4+ CD8- cases. CD3 epsilon mRNA, but not CD3 delta mRNA, was detected in two CD7+ CD5- CD2- cases, while mRNA of neither of the two CD3 molecules was detected in the other tested CD7+ CD5- CD2- cases. In contrast, mRNA of both CD3 epsilon and CD3 delta were detected in all CD7+ CD5+ CD2- cases, indicating that CD7+ CD5- CD2- blasts at least belong to T-lineage. The blasts of two CD7+ CD5- CD2- cases with entire germ-line genes and without mRNA of the three molecules (MPO, CD3 epsilon, and CD3 delta) were regarded as being at an undifferentiated stage prior to their commitment to either T- or myeloid-lineage. The co-expression of the genes of MPO and CD3 epsilon in a CD7+ CD5- CD2- case MPO, CD3 epsilon, and CD3 delta in a CD7+ CD5+ CD2- case suggested the presence of some overlapping phase for T- and myeloid-lineage commitment during immature stages of differentiation. This helps understand the conversion of some T-ALL/LBL cases to acute myeloblastic leukemia (AML).(ABSTRACT TRUNCATED AT 400 WORDS)

Stöckbauer P, Ariyasu T, Starý J, et al.
Establishment and characterization of a novel immature T-ALL cell line, UHKT-42, with TCR beta/delta expression.
Hum Cell. 1994; 7(1):40-6 [PubMed] Related Publications
A novel immature human T-ALL cell line, UHKT-42, was established from a 12 year old male patient with acute undifferentiated leukemia. The cell line expressed surface CD7, CD5 and cytoplasmic CD3 antigens. All other T-lymphocytic antigens were undetectable on the surface or in the cytoplasm of cultured cells. Expression of the T-cell receptor (TCR) beta, TCR delta, CD3 delta and CD3 epsilon genes was detected by Northern blotting in total cellular RNA extracts, however, the expression of TCR alpha and TCR gamma was undetectable. After stimulation by TPA for 3 days, only the appearance of CD25 (Tac antigen) was detected by immunofluorescence and flow cytometry. Secretion of interleukin-2 (IL-2) into the culture media was also detected after stimulation by PHA or TPA, but not in unstimulated cells. These results suggest that UHKT-42 cells are early precursors of T cells, with TCR beta/delta expression.

Heutink P, van Schothorst EM, van der Mey AG, et al.
Further localization of the gene for hereditary paragangliomas and evidence for linkage in unrelated families.
Eur J Hum Genet. 1994; 2(3):148-58 [PubMed] Related Publications
Paragangliomas of the head and neck are slow-growing tumors that rarely show malignant progression. Familial transmission has been described, consistent with an autosomal dominant gene that is maternally imprinted. Clinical manifestations of hereditary paraganglioma are determined by the sex of the transmitting parent. All affected individuals have inherited the disease gene from their father, expression of the phenotype is not observed in the offspring of an affected female or female gene carrier until subsequent transmittance of the gene through a male gene carrier. Recently, we assigned the gene responsible for paragangliomas (PGL) to chromosome 11q23-qter by linkage in a single large Dutch kindred. We now report confirmation of this localization in five unrelated Dutch families with hereditary paragangliomas. On the basis of segregation of haplotypes in the available family material, we localize the PGL locus between markers STMY and CD3D on chromosome 11q22.3-q23.

Pereira MS, Silva ML, Valente AN, et al.
Translocation of CD3D gene in an acute myeloid leukemia (M5) with t(11;17)(q23;21).
Cancer Genet Cytogenet. 1993; 71(2):173-5 [PubMed] Related Publications
Cytogenetic studies in patients with acute leukemia showed structural abnormalities on chromosome 11 at band q23 in five cases. Four of these had acute lymphoblastic leukemia (ALL) associated with t(4;11)(q21;q23) and one case had acute nonlymphoblastic leukemia (ANLL) (M5) associated with t(11;17)(q23;q21). We examined the CD3D and c-ets-1 genes in the t(11;17)(q23;q21) patient to ascertain any association between them and the chromosome change. In situ hybridization results showed that unlike in other studied cases with rearrangements of 11q23, the CD3D gene in the t(11;17)(q23;21) is transposed to the der(17) chromosome, providing evidence for a different breakpoint in the 11q23 region.

Yamaguchi M, Ohno T, Oka K, et al.
Discordant reaction of Leu4 and rabbit anti-human CD3 epsilon in sinonasal 'T'-cell lymphoma.
Int J Hematol. 1993; 59(1):25-30 [PubMed] Related Publications
Twelve cases of sinonasal 'T'-cell lymphoma were studied immunohistologically with a panel of antibodies that included two antibodies to CD3, Leu4 and rabbit anti-human CD3 epsilon. Leu4 was positive in five cases, whereas rabbit anti-human CD3 epsilon was positive in 11. This discordant reaction of the antibodies, suggestive of cytoplasmic CD3 epsilon +, CD3 delta-, and CD3 gamma-, has recently been demonstrated in activated adult natural killer (NK) cells also. Leu4-negative cases had the phenotype CD2+, CD5-, CD7+/-, T-cell receptor (TCR)-, and NK cell markers+, and had non-rearranged TCR genes. These findings suggest that a large group of sinonasal 'T'-cell lymphomas is derived from NK cells.

Kobayashi H, Espinosa R, Thirman MJ, et al.
Heterogeneity of breakpoints of 11q23 rearrangements in hematologic malignancies identified with fluorescence in situ hybridization.
Blood. 1993; 82(2):547-51 [PubMed] Related Publications
Twenty-four patients whose cells contained a variety of 11q23 rearrangements, including translocations, insertions, and an inversion, were studied using fluorescence in situ hybridization with cosmid, phage, and plasmid probes mapped to 11q22-24. In 17 patients, the breakpoints of the common 11q23 translocations involving chromosomes 4, 6, 9, and 19 as well as some uncommon translocations involving 3q23, 17q25, 10p11, and an insertion 10;11 were all located in the breakpoint cluster region of the MLL gene, regardless of age, phenotype of disease, or involvement of a third chromosome. The breakpoints in 11q23 in the other 7 patients with a t(7;11)(p15;q23), inv(11)(p11q23), t(4;11)(q23;q23), der(5)t(5;11)(q13;q23), ins(10;11)(p11;q23q24), t(11;14)(q23;q11), or t(11;18;11) (p15;q21;q23) were located either centromeric to CD3D or telomeric to THY1. Thus, although most 11q23 rearrangements, involve the same breakpoint cluster region of MLL, there is heterogeneity in the breakpoint in some of the rare rearrangements.

Suzushima H, Asou N, Nishimura S, et al.
Double-negative (CD4- CD8-) T cells from adult T-cell leukemia patients also have poor expression of the T-cell receptor alpha beta/CD3 complex.
Blood. 1993; 81(4):1032-9 [PubMed] Related Publications
We present four patients with adult T-cell leukemia (ATL) derived from a novel T-cell subset (CD4-, CD8- [double-negative, DN], T-cell receptor [TCR] alpha beta+). In the ATL cells of these patients, neither gene nor surface expression of CD4 and CD8 antigens was detected. Clinical and laboratory data showed no difference between DN-ATL and CD4+ATL patients. In contrast to typical CD4+ATL cells, DN-ATL cells were shown to express the protein and messenger RNA (mRNA) for S100 beta in immunocytochemical assay and the reverse-transcription polymerase chain reaction assay. The mean fluorescence intensity of the TCR/CD3 complex was extremely low in all four DN-ATL patients as well as in typical CD4+ ATL. All four patients had TCR beta and gamma chain gene rearrangements, with deletion of TCR delta chain gene and mRNA expression for TCR alpha, beta, and CD3 delta but not for TCR gamma and delta chain genes. Thus, CD4- CD8- TCR alpha beta T cells are also a target for human T-cell lymphotrophic virus type I-induced leukemogenesis. In addition, expression of the TCR alpha beta/CD3 complex on the DN-ATL cells was further diminished by the addition of anti-CD3 or anti-TCR alpha beta monoclonal antibody. These results suggest that the decreased expression of the TCR alpha beta/CD3 complex by ATL cells plays a key role in the development of ATL, irrespective of CD4 expression.

Akao Y, Seto M, Yamamoto K, et al.
The RCK gene associated with t(11;14) translocation is distinct from the MLL/ALL-1 gene with t(4;11) and t(11;19) translocations.
Cancer Res. 1992; 52(21):6083-7 [PubMed] Related Publications
We previously demonstrated that the 11q23 breakpoint region, designated the RCK locus, of the RC-K8 B-lymphoma cell line with t(11;14)(q23;q32) is centromeric to PBGD, while breakpoints of infantile leukemia cell lines with t(11;19)(q23;p13) are detectable by pulsed-field gel electrophoresis with the CD3D probe. In the present study, using a probe within 1.0 kilobase of the t(11;14) breakpoint, we isolated a partial complementary DNA clone for the putative RCK gene, which detects a 7.5-kilobase mRNA. Sequence analysis predicted a novel protein of 472 amino acids which demonstrated sequence homology to a translation initiation factor/helicase family. We also isolated a phage clone from the CD3D/G yeast artificial chromosome clone (yB22B2) which detects 11- and 12-kilobase mRNAs, most likely for the MLL/ALL-1 gene associated t(4;11)(q21;q23) and t(11;19)(q23;p13) translocations. By pulsed-field gel electrophoresis after NotI digestion, this recombinant clone is on a 96-kilobase fragment, while RCK and PBGD probes are on a more telomeric 690-kilobase NotI fragment. These results, altogether, suggested that two different genes, RCK and MLL/ALL-1, are associated with 11q23 translocation of hematopoietic tumors.

Cherif D, Der-Sarkissian H, Derré J, et al.
The 11q23 breakpoint in acute leukemia with t(11;19)(q23;p13) is distal to those of t(4;11), t(6;11) and t(9;11).
Genes Chromosomes Cancer. 1992; 4(2):107-12 [PubMed] Related Publications
Thirteen cosmid probes were mapped on the long arm of chromosome 11 between 11q22 and 11q24 by nonradioactive in situ hybridization. Starting with these localizations and those of other probes mapped to 11q23, four acute leukemias with translocations involving 11q23 were studied with the same method. The translocation breakpoints of the t(4;11)(q21;q23), t(6;11)(q27;q23), t(9;11)(p21-p22;q23), and t(11;19)(q23;p13) were confirmed to be distal to CD3D. The probe cC111-304 was proximal to the t(11;19) breakpoint while distal to the breakpoints of the other rearrangements. In view of the diversity of chromosomal abnormalities involving band 11q23, our finding extends the molecular heterogeneity of the breakpoint localization in leukemias with rearrangements involving 11q23.

Akao Y, Seto M, Takahashi T, et al.
Rearrangements on chromosome 11q23 in hematopoietic tumor-associated t(11;14) and t(11;19) translocations.
Cancer Res. 1991; 51(24):6708-11 [PubMed] Related Publications
We previously demonstrated that the breakpoint of t(11;14)(q23;q32) in the RC-K8 B cell lymphoma cell line lies between CD3 and THY1/ETS1 on chromosome 11q23, and we cloned this region and named it the rck locus. Pulsed-field gel electrophoresis showed that the rck probe B (distal to the breakpoint) and the porphobilinogen deaminase (PBGD) probe detect the same germ line band and also the same rearranged band when DNA from RC-K8 cells was digested with NotI enzyme. Furthermore, Southern blot analysis with somatic cell hybrids showed that the PBGD gene moved to the 14q+chromosome, which confirmed PBGD to be more distal to the centromere than the rck locus. These data allowed us to construct the following order of genes: 11 cen-q23-CD3-rck-PBGD-THY1/ETS1. In this study, three infantile leukemia cell lines with t(11;19)(q23;p13) translocation were also analyzed by pulsed-field gel electrophoresis. CD3D probe detected the rearranged bands in DNA from two of them after digestion with NotI and SacII enzymes, demonstrating that the breakpoints of both cell lines were estimated to be within 360 kilobases of CD3D.

Ziemin-van der Poel S, McCabe NR, Gill HJ, et al.
Identification of a gene, MLL, that spans the breakpoint in 11q23 translocations associated with human leukemias.
Proc Natl Acad Sci U S A. 1991; 88(23):10735-9 [PubMed] Free Access to Full Article Related Publications
Recurring chromosomal translocations involving chromosome 11, band q23, have been observed in acute lymphoid leukemias and especially in acute myeloid leukemias. We recently showed that breakpoints in four 11q23 translocations, t(4;11)(q21;q23), t(6;11)(q27;q23), t(9;11)(p22;q23), and t(11;19)(q23;p13.3), were contained within a yeast artificial chromosome clone bearing the CD3D and CD3G gene loci. We have identified within the CD3 yeast artificial chromosome a transcription unit that spans the breakpoint junctions of the 4;11, 9;11, and 11;19 translocations, and we describe two other, related transcripts that are upregulated in the RS4;11 cell line. We have named this gene MLL (myeloid/lymphoid, or mixed-lineage, leukemia.

Suzushima H, Hattori T, Asou N, et al.
Discordant gene and surface expression of the T-cell receptor/CD3 complex in adult T-cell leukemia cells.
Cancer Res. 1991; 51(22):6084-8 [PubMed] Related Publications
Cell surface expression of the T-cell receptor (TCR)/CD3 complex on the cells from 11 acute type adult T-cell leukemia (ATL) and 4 lymphoma type ATL patients was examined by flow cytometry. Cells from 10 of 11 acute ATL patients were TCR alpha beta+ and CD3+, and their mean fluorescence intensities were low (TCR alpha beta, 25.3-84.6; CD3, 22.8-87.8). Cells from two of four lymphoma type ATL did not express this complex, and the other two were CD3+, TCR alpha beta-. In contrast, the mean fluorescence intensity of the TCR/CD3 complex in cells from a patient with T4 chronic lymphocytic leukemia was not low (TCR alpha beta, 129.9; CD3, 117.1). mRNA expressions of the TCR alpha, beta, and CD3 gamma, delta, epsilon, and zeta chains were examined by Northern blots. ATL cells from two acute and two lymphoma types expressed amounts of this complex equal to or greater than those expressed by T4 chronic lymphocytic leukemia. CD3 delta and TCR beta mRNA in ATL and T4 chronic lymphocytic leukemia cells were equally stable to actinomycin D treatment. The synthesis of CD3 zeta protein by ATL cells was detected by Western blotting assay. On the basis of these findings, we discuss the possible involvement of the TCR/CD3 complex in activation of ATL cells.

Cotter FE, Lillington D, Hampton G, et al.
Gene mapping by microdissection and enzymatic amplification: heterogeneity in leukaemia associated breakpoints on chromosome 11.
Genes Chromosomes Cancer. 1991; 3(1):8-15 [PubMed] Related Publications
A new strategy for mapping chromosome translocation breakpoints in relation to known genes has been developed. This approach is based on the amplification by the polymerase chain reaction (PCR) of specific target sequences from small numbers of microdissected chromosome fragments. This method has been applied to leukaemia-associated translocations affecting the q23 region of chromosome 11. In two independent leukaemias, the t(6;11) translocation was distinguished from the t(9;11) and t(4;11) translocations by demonstrating that the former breakpoint on chromosome 11 lay proximal to the CD3D gene while the latter breakpoints lay distal to CD3D. All three translocation breakpoints were found to lie proximal to ETSI and THYI. The data suggest that although these leukaemia-associated breakpoints on chromosome 11 are cytogenetically identical they may involve disruption of different genes. This approach offers a rapid alternative to mapping by hybridisation of probes either in situ to chromosomes or to somatic cell hybrids containing the appropriate derivative chromosomes.

Das S, Cotter FE, Gibbons B, et al.
CD3G is within 200 kb of the leukemic t(4;11) translocation breakpoint.
Genes Chromosomes Cancer. 1991; 3(1):44-7 [PubMed] Related Publications
The t(4;11)(q21;q23) has been associated with acute lymphocytic leukemia (ALL) especially in infants. The t(4;11) breakpoint on chromosome 11 is cytogenetically indistinguishable from breakpoints for other leukemia-associated translocations affecting 11q23. The molecular basis of the t(4;11) is unknown although a number of genes have been mapped to 11q23. The CD3D, G, and E genes have been positioned proximal to the 11q23 breakpoint of the 4;11 translocation while the THY1 and ETS1 genes have been mapped distal to this breakpoint. We report evidence that CD3G is within 200 kb of the 4;11 breakpoint as observed by pulsed field gel analysis. A rearrangement of the CD3G gene has been observed in a cell line derived from a patient with the t(4;11) translocation and in a hybrid cell line containing the derivative 11q chromosome derived from this cell line, using the restriction enzymes SacII and ClaI. Similar rearrangements using SacII were observed in 2 further patients with ALL and the t(4;11) translocation. No rearrangements in the same DNA were observed using ETS1, THY1, and D11S29 and a range of rare cutter restriction enzymes. CD3G thus provides a tool for the cloning and analysis of the 4;11 translocation, and poses a question of its possible involvement at long range with this translocation.

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