The C-MYB locus is involved in chromosomal translocation and genomic duplications in human T-cell acute leukemia (T-ALL), the translocation defining a new T-ALL subtype in very young children

Blood ◽  
2007 ◽  
Vol 110 (4) ◽  
pp. 1251-1261 ◽  
Author(s):  
Emmanuelle Clappier ◽  
Wendy Cuccuini ◽  
Anna Kalota ◽  
Antoine Crinquette ◽  
Jean-Michel Cayuela ◽  
...  
Keyword(s):  
T Cell ◽  
Acute Leukemia ◽  
Large Scale ◽  
Insertional Mutagenesis ◽  
Cell Lineage ◽  
Chromosomal Translocation ◽  
Myb Transcription Factor ◽  
Comparative Genomic ◽  
Human T Cell ◽  
A Genome

AbstractThe C-Myb transcription factor is essential for hematopoiesis, including in the T-cell lineage. The C-Myb locus is a common site of retroviral insertional mutagenesis, however no recurrent genomic involvement has been reported in human malignancies. Here, we identified 2 types of genomic alterations involving the C-MYB locus at 6q23 in human T-cell acute leukemia (T-ALL). First, we found a reciprocal translocation, t(6;7)(q23;q34), that juxtaposed the TCRB and C-MYB loci (n = 6 cases). Second, a genome-wide copy-number analysis by array-based comparative genomic hybridization (array-CGH) identified short somatic duplications that include C-MYB (MYBdup, n = 13 cases of 84 T-ALL, 15%). Expression analysis, including allele-specific approaches, showed stronger C-MYB expression in the MYB-rearranged cases compared with other T-ALLs, and a dramatically skewed C-MYB allele expression in the TCRB-MYB cases, which suggests that a translocation-driven deregulated expression may overcome a cellular attempt to down-regulate C-MYB. Strikingly, profiling of the T-ALLs by clinical, genomic, and large-scale gene expression analyses shows that the TCRB-MYB translocation defines a new T-ALL subtype associated with a very young age for T-cell leukemia (median, 2.2 years) and with a proliferation/mitosis expression signature. By contrast, the MYBdup alteration was associated with the previously defined T-ALL subtypes.

Interrogating CD8+ T cell reactivity on a genome-wide scale

2019 ◽  
Vol 11 (506) ◽  
pp. eaaz0302
Author(s):  
Kamila Naxerova
Keyword(s):  
T Cell ◽  
Large Scale ◽  
Cd8 T Cell ◽  
Cell Reactivity ◽  
Human T Cell ◽  
Genome Wide ◽  
A Genome ◽  
T Cell Antigens ◽  
Wide Scale ◽  
T Cell Reactivity

A new method enables large-scale identification of human T cell antigens.

scholarly journals A third tal-1 promoter is specifically used in human T cell leukemias.

1992 ◽  
Vol 176 (4) ◽  
pp. 919-925 ◽  
Author(s):  
O Bernard ◽  
O Azogui ◽  
N Lecointe ◽  
F Mugneret ◽  
R Berger ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Lineage ◽  
Chromosomal Translocation ◽  
Cell Receptor ◽  
Genomic Alteration ◽  
Normal Bone ◽  
Human T Cell ◽  
Exon 4 ◽  
T Cell Lines ◽  
Fourth Exon

A common feature of T cell acute lymphoblastic leukemias (T-ALLs) is the presence of structural alteration of the 5' part of the tal-1 locus, localized on chromosomal band 1p32. These alterations consist of either a t(1;14)(p32;q11) chromosomal translocation (3% of T-ALLs) or tald submicroscopic deletion (12-25% additional T-ALLs). We have characterized a case of T-ALL with t(1;14)(p32;q11) in which, unlike the majority of t(1;14), the recombination with the T cell receptor delta elements affected the 3' side of the tal-1 locus. In this case, tal-1 transcription is initiated from a promoter located within the fourth exon similarly to the DU 528 cell line. In a T-ALL bearing a t(1;14) affecting the 5' part of tal-1, two types of tal-1 transcripts were observed, namely those probably initiated from the D delta region juxtaposed to tal-1 by the translocation, and those from the exon 4 promoter. It is interesting that this exon 4 promotion was also found in leukemic T cell lines and T-ALL samples without apparent tal-1 genomic alteration. In contrast, no transcript initiated from the exon 4 promoter was found in T-ALL with tald1 or tald2 deletion. In these cells, tal-1 is expressed via SIL-tal-1 fused transcripts. Finally, this exon 4 initiation was detected neither in normal bone marrow, nor in malignant cells from the erythroid/megakaryocytic lineages. Taken as a whole, these data suggest that the exon 4 promoter is specifically active in T cell lineage.

scholarly journals A primary human T-cell spectral library to facilitate large scale quantitative T-cell proteomics

2020 ◽  
Vol 7 (1) ◽  
Author(s):  
Harshi Weerakoon ◽  
Jeremy Potriquet ◽  
Alok K. Shah ◽  
Sarah Reed ◽  
Buddhika Jayakody ◽  
...  
Keyword(s):  
T Cell ◽  
Large Scale ◽  
Large Data ◽  
Spectral Library ◽  
Proteomics Data ◽  
Cell Library ◽  
Public Resource ◽  
Human T Cell ◽  
Theoretical Mass ◽  
Current Resource

AbstractData independent analysis (DIA) exemplified by sequential window acquisition of all theoretical mass spectra (SWATH-MS) provides robust quantitative proteomics data, but the lack of a public primary human T-cell spectral library is a current resource gap. Here, we report the generation of a high-quality spectral library containing data for 4,833 distinct proteins from human T-cells across genetically unrelated donors, covering ~24% proteins of the UniProt/SwissProt reviewed human proteome. SWATH-MS analysis of 18 primary T-cell samples using the new human T-cell spectral library reliably identified and quantified 2,850 proteins at 1% false discovery rate (FDR). In comparison, the larger Pan-human spectral library identified and quantified 2,794 T-cell proteins in the same dataset. As the libraries identified an overlapping set of proteins, combining the two libraries resulted in quantification of 4,078 human T-cell proteins. Collectively, this large data archive will be a useful public resource for human T-cell proteomic studies. The human T-cell library is available at SWATHAtlas and the data are available via ProteomeXchange (PXD019446 and PXD019542) and PeptideAtlas (PASS01587).

scholarly journals The isolation and sequence of a novel gene from a human functional T cell line.

1987 ◽  
Vol 165 (3) ◽  
pp. 601-614 ◽  
Author(s):  
J Jongstra ◽  
T J Schall ◽  
B J Dyer ◽  
C Clayberger ◽  
J Jorgensen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Lines ◽  
Cdna Clone ◽  
Cell Lineage ◽  
Subtractive Hybridization ◽  
Protein Product ◽  
Novel Gene ◽  
Human T Cell

Using a subtractive hybridization procedure we have constructed a cDNA library enriched for sequences present in functional human T cell lines, but not in human EBV-transformed B cell lines. We have isolated a cDNA clone, AH2-519, representing a novel gene, designated 519. This novel gene is expressed in functional human cytolytic and Th cell lines but not in a variety of other cell lines, including several long-term human T cell tumor lines. The expression of gene 519 is inducible in cultures of normal human PBL using antigenic or mitogenic stimulation. Neither the DNA sequence determined from a full-length cDNA clone overlapping with clone AH2-519 nor the amino acid sequence of its predicted protein product has significant homology to published sequences in the GenBank or NBRF databases. The restricted expression of gene 519 suggests that its gene product is involved in the growth and/or differentiation of normal T cells. The data also show that normal, nontransformed, functional T cells express gene products that can not be readily identified in long-term tumor lines of the same cell lineage.

scholarly journals Profile of a Serial Killer: Cellular and Molecular Approaches to Study Individual Cytotoxic T-Cells following Therapeutic Vaccination

2011 ◽  
Vol 2011 ◽  
pp. 1-21 ◽  
Author(s):  
Emanuela M. Iancu ◽  
Petra Baumgaertner ◽  
Sébastien Wieckowski ◽  
Daniel E. Speiser ◽  
Nathalie Rufer
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Biology ◽  
Large Scale ◽  
T Cell Responses ◽  
Serial Killer ◽  
Phase Iii ◽  
Cell Responses ◽  
T Cell Vaccination ◽  
Human T Cell

T-cell vaccination may prevent or treat cancer and infectious diseases, but further progress is required to increase clinical efficacy. Step-by-step improvements of T-cell vaccination in phase I/II clinical studies combined with very detailed analysis of T-cell responses at the single cell level are the strategy of choice for the identification of the most promising vaccine candidates for testing in subsequent large-scale phase III clinical trials. Major aims are to fully identify the most efficient T-cells in anticancer therapy, to characterize their TCRs, and to pinpoint the mechanisms of T-cell recruitment and function in well-defined clinical situations. Here we discuss novel strategies for the assessment of human T-cell responses, revealing in part unprecedented insight into T-cell biology and novel structural principles that govern TCR-pMHC recognition. Together, the described approaches advance our knowledge of T-cell mediated-protection from human diseases.

scholarly journals Antigenic Equivalence of Human T-Cell Responses toMycobacterium tuberculosis-Specific RD1-Encoded Protein Antigens ESAT-6 and Culture Filtrate Protein 10 and to Mixtures of Synthetic Peptides

2000 ◽  
Vol 68 (6) ◽  
pp. 3314-3321 ◽  
Author(s):  
Sandra M. Arend ◽  
Annemieke Geluk ◽  
Krista E. van Meijgaarden ◽  
Jaap T. van Dissel ◽  
Michael Theisen ◽  
...  
Keyword(s):  
T Cell ◽  
Culture Filtrate ◽  
Large Scale ◽  
Mononuclear Cells ◽  
Genomic Region ◽  
Protein Antigens ◽  
Peripheral Blood Mononuclear ◽  
Human T Cell ◽  
Peptide Mixtures ◽  
Culture Filtrate Protein

ABSTRACT The early secreted antigenic target 6-kDa protein (ESAT-6) and culture filtrate protein 10 (CFP-10) are promising antigens for reliable immunodiagnosis of tuberculosis. Both antigens are encoded by RD1, a genomic region present in all strains of Mycobacterium tuberculosis and M. bovis but lacking in all M. bovis bacillus Calmette-Guérin vaccine strains. Production and purification of recombinant antigens are laborious and costly, precluding rapid and large-scale testing. Aiming to develop alternative diagnostic reagents, we have investigated whether recombinant ESAT-6 (rESAT-6) and recombinant CFP-10 (rCFP-10) can be replaced with corresponding mixtures of overlapping peptides spanning the complete amino acid sequence of each antigen. Proliferation of M. tuberculosis-specific human T-cell lines in response to rESAT-6 and rCFP-10 and that in response to the corresponding peptide mixtures were almost completely correlated (r = 0.96,P < 0.0001 for ESAT-6; r = 0.98,P < 0.0001 for CFP-10). More importantly, the same was found when gamma interferon production by peripheral blood mononuclear cells in response to these stimuli was analyzed (r = 0.89, P < 0.0001 for ESAT-6;r = 0.89, P < 0.0001 for CFP-10). Whole protein antigens and the peptide mixtures resulted in identical sensitivity and specificity for detection of infection with M. tuberculosis. The peptides in each mixture contributing to the overall response varied between individuals with different HLA-DR types. Interestingly, responses to CFP-10 were significantly higher in the presence of HLA-DR15, which is the major subtype of DR2. These results show that mixtures of synthetic overlapping peptides have potency equivalent to that of whole ESAT-6 and CFP-10 for sensitive and specific detection of infection with M. tuberculosis, and peptides have the advantage of faster production at lower cost.

scholarly journals Genomic Amplification of an Endogenous Retrovirus in Zebrafish T-Cell Malignancies

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
J. Kimble Frazer ◽  
Lance A. Batchelor ◽  
Diana F. Bradley ◽  
Kim H. Brown ◽  
Kimberly P. Dobrinski ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Insertional Mutagenesis ◽  
Chromosomal Rearrangements ◽  
Fish Tissue ◽  
Endogenous Retrovirus ◽  
Comparative Genomic ◽  
Genomic Amplification ◽  
Thymic Tissue ◽  
T Cell Leukemogenesis

Genomic instability plays a crucial role in oncogenesis. Somatically acquired mutations can disable some genes and inappropriately activate others. In addition, chromosomal rearrangements can amplify, delete, or even fuse genes, altering their functions and contributing to malignant phenotypes. Using array comparative genomic hybridization (aCGH), a technique to detect numeric variations between different DNA samples, we examined genomes from zebrafish (Danio rerio) T-cell leukemias of three cancer-prone lines. In all malignancies tested, we identified recurring amplifications of a zebrafish endogenous retrovirus. This retrovirus, ZFERV, was first identified due to high expression of proviral transcripts in thymic tissue from larval and adult fish. We confirmed ZFERV amplifications by quantitative PCR analyses of DNA from wild-type fish tissue and normal and malignantD. rerioT cells. We also quantified ZFERV RNA expression and found that normal and neoplastic T cells both produce retrovirally encoded transcripts, but most cancers show dramatically increased transcription. In aggregate, these data imply that ZFERV amplification and transcription may be related to T-cell leukemogenesis. Based on these data and ZFERV’s phylogenetic relation to viruses of the murine-leukemia-related virus class of gammaretroviridae, we posit that ZFERV may be oncogenic via an insertional mutagenesis mechanism.

scholarly journals Distinct molecular forms of human T cell receptor gamma/delta detected on viable T cells by a monoclonal antibody.

1988 ◽  
Vol 167 (5) ◽  
pp. 1625-1644 ◽  
Author(s):  
J Borst ◽  
J J van Dongen ◽  
R L Bolhuis ◽  
P J Peters ◽  
D A Hafler ◽  
...  
Keyword(s):  
T Cell ◽  
T Lymphocytes ◽  
Peripheral Blood ◽  
Cell Lineage ◽  
Cell Receptor ◽  
Cytolytic Activity ◽  
Molecular Forms ◽  
Gamma Delta ◽  
Gamma Chain ◽  
Human T Cell

A second type of TCR molecule has been identified on human and murine T lymphocytes, which involves the protein products of the gamma and delta genes. T lymphocytes bearing this receptor may constitute a separate cell lineage with a distinct immune function. We have produced an mAb, which specifically detects human TCR-gamma/delta in native as well as denatured states, this in contrast to previously used anti-gamma chain peptide sera, which only reacted with denatured protein. The receptor occurs in different molecular forms, with or without interchain disulphide bonds, in which a delta chain may or may not be detected by cell surface iodination. The mAb is reactive with all these receptor forms. Therefore, this antibody could be used to determine the expression of TCR-gamma/delta on viable human T lymphocytes. In normal individuals, TCR-gamma/delta was found on a subset composing 2-7% of CD3+ lymphocytes in peripheral blood and 0.1-1.0% in thymus. The majority of these cells do not express the CD4 or CD8 antigens, although a significant percentage of CD8+ cells was found. TCR-gamma/delta+ cells in peripheral blood are resting lymphocytes, as judged by ultrastructural analysis. T cell clones with different receptor types can display MHC-nonrestricted cytolytic activity, which is shown to be induced by the culture conditions, most likely by growth factors such as IL-2. This strongly suggests that TCR-gamma/delta does not play a role in target cell recognition in MHC-nonrestricted cytotoxicity. The anti-TCR-gamma/delta antibody can specifically induce cytotoxic activity in clones expressing the receptor, but in addition inhibit growth factor induced cytotoxicity, which indicates a regulatory role of the TCR-gamma/delta/CD3 complex in MHC-nonrestricted cytotoxicity.

scholarly journals Very high prevalence of infection with the human T cell leukaemia virus type 1c in remote Australian Aboriginal communities: Results of a large cross-sectional community survey

2021 ◽  
Vol 15 (12) ◽  
pp. e0009915
Author(s):  
Lloyd Einsiedel ◽  
Hai Pham ◽  
Mohammad Radwanur Talukder ◽  
Kerry Taylor ◽  
Kim Wilson ◽  
...  
Keyword(s):  
T Cell ◽  
Virus Type ◽  
Large Scale ◽  
Aboriginal People ◽  
Cell Leukaemia ◽  
Aboriginal Communities ◽  
Leukaemia Virus ◽  
Human T Cell ◽  
Wide Range ◽  
Central Australia

Infection with the human T cell leukaemia virus type 1 (HTLV-1) subtype C is endemic among Aboriginal people in central Australia. To provide insights into the risk factors for transmission, we conducted the first large-scale, community-based prevalence study in seven remote Aboriginal communities. Residents >2 years old were invited to participate in the study between August 2014 and June 2018. HTLV-1 infection was defined as a positive western blot (WB) test or a positive HTLV-1 PCR. 720 community residents participated in the study (children <15 years, 142; adults, 578). Prevalences for children and adults were 3.5% (5/142) and 36.8% (213/578), respectively, reaching 49.3% (106/215) for those older than 45 years. A wide range of proviral loads were measured for both asymptomatic and symptomatic participants with no difference within groups according to age or gender; however, median PVL was 1.34 log10 higher for symptomatic participants. The adult prevalence of HTLV-1 infection in central Australia is the highest reported worldwide. Sexual contact is likely to be the predominant mode of transmission.

Oncogenic activation of the Lck protein accompanies translocation of the LCK gene in the human HSB2 T-cell leukemia

1994 ◽  
Vol 14 (4) ◽  
pp. 2429-2437
Author(s):  
D D Wright ◽  
B M Sefton ◽  
M P Kamps
Keyword(s):  
T Cell ◽  
Cell Lines ◽  
T Cell Activation ◽  
Cell Activation ◽  
Chromosomal Translocation ◽  
Cell Receptor ◽  
Kinase Domain ◽  
3T3 Fibroblasts ◽  
Human T Cell ◽  
T Cell Lines

The tyrosine protein kinase p56lck transduces signals important for antigen-induced T-cell activation. In transgenic mice, p56lck is oncogenic when overexpressed or expressed as a mutant, catalytically activated enzyme. In humans, the LCK gene is located at the breakpoint of the t(1;7)(p34;q34) chromosomal translocation. This translocation positions the beta T-cell receptor constant region enhancer upstream of the LCK gene without interrupting the LCK coding sequences, and a translocation of this sort occurs in both the HSB2 and the SUP-T-12 T-cell lines. We have found that, although the level of the p56lck protein in HSB2 cells is elevated approximately 2-fold in comparison with that in normal T-cell lines, total cellular tyrosine protein phosphorylation is elevated approximately 10-fold. Increased levels of phosphotyrosine in HSB2 cells resulted from mutations in the LCK gene that activated its function as a phosphotransferase and converted it into a dominant transforming oncogene. The oncogenic p56lck in HSB2 cells contained one amino acid substitution within the CD4/CD8-binding domain, two substitutions in the kinase domain, and an insertion of Gln-Lys-Pro (QKP) between the SH2 and kinase domains. In NIH 3T3 fibroblasts, three of these mutations cooperated to produce the fully oncogenic form of this p56lck variant. These results suggest that mutation of LCK may contribute to some human T-cell leukemias.

Sign in / Sign up

Export Citation Format

Share Document