Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: KEGG:D01078 (TEL)
781 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In myeloid and lymphoid leukemias recurrent chromosomal aberrations can be detected in chromosome region 12p13. We characterized the genes involved in t(12;22) (p13;q11) in two patients with myeloid leukemia and one with myelodysplastic syndrome (MDS). MN1, a gene on chromosome 22q11 was shown to be fused to TEL, a member of the family of ETS transcription factors on chromosome 12p13. The translocation results in transcription of the reciprocal fusion mRNAs, MN1-TEL and TEL-MN1, of which MN1-TEL is likely to encode an aberrant transcription factor containing the ETS DNA-binding domain of TEL. In addition to fusion of TEL to the PDGF beta receptor in t(5;12) in chronic myelomonocytic leukemia (CMML), our data suggest that the involvement of this protein in myeloid leukemogenesis could be dual; its isolated protein-protein dimerization and DNA-binding domains may be crucial for the oncogenic activation of functionally different fusion proteins.
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PMID:Translocation (12;22) (p13;q11) in myeloproliferative disorders results in fusion of the ETS-like TEL gene on 12p13 to the MN1 gene on 22q11. 773 5

A recurrent t(12;21)(p13;q22) has recently been described in human acute lymphoblastic leukemias (ALLs). This translocation fuses TEL and AML1, two genes previously cloned from translocation breakpoints in myeloid leukemias. In addition, allelic loss of the TEL gene can be detected in 15% to 22% of childhood ALLs. In the present study, we have sought allelic deletions of TEL and the presence of the t(12;21) in 50 children with B-lineage ALL, using a combination of microsatellite typing, fluorescent in situ hybridization (FISH), and analysis of the fusion transcripts resulting from the TEL-AML1 gene fusion. Our results indicate that the association between the t(12;21) and the deletion of the nontranslocated allele of TEL is among the most frequent abnormalities observed in B-lineage ALLs. FISH analysis using several cosmid probes showed that, in one patient with a t(12;21) translocation involving TEL, the second allele had an intragenic deletion. This observation points to TEL as the actual target of 12p12-13 deletions in patients that associate a t(12;21) with a deletion. The TEL-AML1 fusion RNA was found in all patients with the t(12;21) whereas the reciprocal AML1-TEL transcript was only found in a subset of patients, suggesting that only the protein product encoded by TEL-AML1 is likely to play a role in leukemogenesis. The observation that, in two patients with the t(12;21), a deletion of TEL was only present in a subclone indicates that this deletion was a secondary event that occurred after the translocation. The frequent occurrence of TEL deletions in patients with t(12;21) suggests that the deletion of the normal TEL allele subsequent to the t(12;21) provides a further proliferative advantage to leukemic cells.
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PMID:The 12;21 translocation involving TEL and deletion of the other TEL allele: two frequently associated alterations found in childhood acute lymphoblastic leukemia. 863 9

Recently, a new recurrent t(12;21)(pl3;q22) has been identified in a B-cell lineage childhood acute lymphoblastic leukemia (ALL). The translocation results in a fusion of two known genes, ETV6/TEL (12p13) and AML1 (21q22), previously shown to be involved in the pathogenesis of myeloid disorders. We report results of cytogenetic fluorescence in situ hybridization and molecular studies of a B-cell childhood common ALL with a cryptic 12;21 translocation. Aberrations identified in this case involve both chromosomes 12 and include not only the ETV6-AML1 gene fusion and two different microdeletions of ETV6 but also the hemizygous loss of CDKN1B, D12S119, and KRAS2 loci and a putative rearrangement of the second CDKN1B allele as a result of an inv(12)(p13q24). Moreover, it was shown that the AML1-ETV6 reciprocal chimeric transcript was not present in the malignant cells, and hence may not play a major role in leukemogenesis. In addition, the putative loss of wild-type function of CDKN1B and ETV6 could indicate a synergistic effect of both genes in the pathogenesis of this leukemia case.
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PMID:Biallelic alterations of both ETV6 and CDKN1B genes in a t(12;21) childhood acute lymphoblastic leukemia case. 865 12

The t(12;21) translocation is present in up to 30% of childhood B-cell acute lymphoblastic and fuses a potential dimerization motif from the ets-related factor TEL to the N terminus of AML1. The t(12;21) translocation encodes a 93-kDa fusion protein that localizes to a high-salt- and detergent-resistant nuclear compartment. This protein binds the enhancer core motif, TGTGGT, and interacts with the AML-1-binding protein, core-binding factor beta. Although TEL/AML-1B retains the C-terminal domain of AML-1B that is required for transactivation of the T-cell receptor beta enhancer, it fails to activate transcription but rather inhibits the basal activity of this enhancer. TEL/AML-1B efficiently interferes with AML-1B dependent transactivation of the T-cell receptor beta enhancer, and coexpression of wild-type TEL does not reverse this inhibition. The N-terminal TEL helix-loop-helix domain is essential for TEL/AML-1B-mediated repression. Thus, the t(12;21) fusion protein dominantly interferes with AML-1B-dependent transcription, suggesting that the inhibition of expression of AML-1 genes is critical for B-cell leukemogenesis.
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PMID:The t(12;21) translocation converts AML-1B from an activator to a repressor of transcription. 865 8

AML-1B is targeted directly and indirectly in multiple chromosomal translocations in myeloid and B-cells. The AML-1/ETO and TEL/AML-1 fusion proteins, created by the t(8;21) and t(12;21) respectively, disrupt AML-1B-dependent transcription. Recently, two human members of the runt homology domain family of transcription factors have been identified, AML-2 and AML-3, which also regulate transcription through enhancer core motifs. If multiple factors regulate transcription through the same site, a dominant interfering protein may be required to promote leukemogenesis, rather than the inactivation of both AML1 alleles. To determine which AML family proteins are active in hematopoietic cells, we developed antisera specific to each family member for use in gel mobility shift assays. We have found that AML-1B is the major DNA binding activity in T-cell lines, while both AML-1B and AML-2 are expressed in myeloid and B-cell lines. AML-1B represents most of the active protein in the mouse thymus, whereas AML-1 and AML-2 are equally expressed in the mouse spleen. AML-3 is expressed at very low levels in a single myeloid cell line, 32D.3, and is the only core binding activity present in Buffalo rat liver cells. We demonstrate that AML-2-dependent transactivation mediated by enhancer core motifs is inhibited by the AML-1/ETO and TEL/AML-1 fusion proteins. This indicates that the t(8;21) and t(12;21) fusion proteins inhibit transcriptional activation by the AML-1 transcription factor family, and in so doing contributes to leukemogenesis.
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PMID:AML-2 is a potential target for transcriptional regulation by the t(8;21) and t(12;21) fusion proteins in acute leukemia. 871 Mar 69

Chromosomal abnormalities involving the short arm of chromosome 12 have been frequently observed in a broad spectrum of hematological malignancies. Recently, a gene located in this chromosomal region and implicated in leukemogenesis was identified. The gene, called ETV6 (previously known as TEL) is a new member of the ETS family, a group of genes thought to act as transcriptional activators. The gene spans 240 kb and consists of eight exons coding for a helix-loop-helix (HLH) and a DNA-binding domain. ETV6 was originally identified in a t(5;12)(q33;p13) occurring in a chronic myelomonocytic leukemia (CMML). Recent reports, however, show its involvement in a growing number of translocations associated with myeloid as well as lymphoid leukemias. At the molecular level fusions of ETV6 with PDGFRB (5q33), ABL (9q34), MNI(22q11) and AML1(21q22) have already been identified. Analysis of these chimeric proteins indicates that distinct domains of ETV6 can be involved in different fusion products, thus ETV6 can provide transcriptional and dimerization properties for partner genes, or the gene itself can act as an altered transcriptional factor. At least two clinico-pathological entities associated with ETV6 rearrangements have emerged as distinct disorders. The first one is a chronic myeloid malignancy characterized by t(5;12)(q33;p13), monocytosis and/or eosinophilia. The second entity is a type of childhood acute lymphoblastic leukemia (ALL) hallmarked by t(12;21)(p13;q22), and is shown to be the most frequent but cytogenetically largely undetectable chromosomal anomaly in childhood ALL.
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PMID:ETV6 gene rearrangements in hematopoietic malignant disorders. 903 Nov 9

A short review of chromosome 21 abnormalities in acute lymphoblastic leukemia (ALL) is presented. Trisomy and polysomy 21 are nonrandom anomalies that are frequently observed in ALL. Their occurrence, although not specific, as well as the high incidence of acute leukemia in subjects with constitutional trisomy 21, suggests that chromosome 21 plays a particular role in leukemogenesis. More specific to ALL, t(12;21)(p13;q22), resulting in a fusion TEL-AML1, gene has recently been shown to be the most frequent translocation in childhood B-cell lineage ALL (20-30% of cases). In addition, the importance of analysis of marker chromosomes with fluorescence in situ hybridization (FISH) techniques is underscored as partial amplifications or rearrangements of chromosome 21 may be implicated.
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PMID:Acute lymphoblastic leukemia and chromosome 21. 907 85

ETV6 (TEL) is rearranged in various types of hematologic malignancies. The B-cell precursor acute lymphoblastic leukemia (ALL) cell line SUP-B2 has a t(6;12)(q23;p13) involving ETV6 at 12p13 and a submicroscopic deletion of the other ETV6 allele. The reciprocal translocation results in the fusion of ETV6 to a previously unknown gene at 6q23, which we named STL (six-twelve leukemia gene). Both reciprocal fusion transcripts can be detected: On the der(6) chromosome, the ETV6/STL mRNA shows an apparently out of frame fusion of ETV6 at nucleotide 187 to STL, which would result in the addition of 14 amino acids to the first 54 amino acids of ETV6. On the der(12) chromosome three different variants of the STL/ETV6 fusion mRNA could be detected; variable size segments were inserted at the breakpoint between STL and ETV6 exon 3. One of these variants could give rise to a protein in which the first 54 amino acids of ETV6 are replaced by 12 amino acids from one of the STL short open reading frames. Sequence analysis of a 1.4 kb STL cDNA clone from a skeletal muscle library revealed no long open reading frames. This cell line will be very useful in studying the different mechanisms by which alterations of ETV6 contribute to leukemogenesis and in testing the hypothesis that ETV6 might act as a tumor suppressor gene.
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PMID:A t(6;12)(q23;p13) results in the fusion of ETV6 to a novel gene, STL, in a B-cell ALL cell line. 908 65

The ETV6 (also known as TEL) gene on chromosome 12p13 is the target of a number of translocations associated with various hematologic malignancies. The contribution of ETV6 to leukemogenesis occurs through different mechanisms that involve either its helix-loop-helix dimerization domain or its E26 transformation-specific (ETS) DNA-binding domain. Using fluorescence in situ hybridization we characterized seven new ETV6 rearrangements in chronic myeloid leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, and non-Hodgkin's lymphoma. These aberrations, not always discernible at the cytogenetic level, include a t(5;12)(q31;p13), t(6;12;17)(p21;p13;q25), t(7;12)(p15;p13), t(7;12)(p12;p13), t(7;12)(q36;p13), t(12;13)(p13;q12), and a not completely defined t(12;?)(p13;?). Loss or disruption of the second ETV6 allele by a del(12)(p12p13) or by an intragenic ETV6 deletion was detected in two cases. In six cases the 12p13 breakpoint occurred in the 5' end of ETV6, upstream to exons encoding the HLH domain, whereas the remaining case had a breakpoint between the exons coding for the HLH domain and the exons coding for the ETS domain of ETV6. These observations provide further evidence for the multiple contributions of ETV6 in the pathogenesis of a wide range of hematologic malignancies.
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PMID:Fluorescence in situ hybridization characterization of new translocations involving TEL (ETV6) in a wide spectrum of hematologic malignancies. 945 71

The t(12;21) (p13;q22) is observed in approximately 20-25% of childhood B-lineage acute lymphoblastic leukemia (ALL) cases in both Asian and Caucasian populations. This translocation results in the fusion of TEL, a recently described ETS-like gene on 12p13, and AML1, which was shown to be involved in the formation of fusion genes with ETO and EVI1 in myeloid leukemias. Fluorescence in situ hybridization (FISH) and reverse transcriptase-polymerase chain reaction (RT-PCR) analysis are useful in detecting this translocation which is not readily identified with routine cytogenetic techniques. The t(12;21) is associated with a distinct subgroup of patients characterized by an age between 1 and 10 years, an early B immunophenotype, and a good prognosis. A high incidence of the deletion of non-translocated TEL is another characteristic of leukemic cells with this translocation. TEL-AML1 hybrid protein thought to be critical in leukemogenesis possesses the HLH domain of TEL fused to almost the entire AML1 protein, although the detailed mechanisms of leukemogenesis remain obscure. RT-PCR combined with FISH analysis of posttreatment samples appears to be useful in detecting early relapse or minimal residual disease and thus, is expected to optimize the treatment strategy for patients with t(12;21).
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PMID:Detection of the Der (21)t(12;21) chromosome forming the TEL-AML1 fusion gene in childhood acute lymphoblastic leukemia. 949 2


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