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)

Chromosomal translocations involving the human 12p13 band frequently affect the TEL gene, usually resulting in gene fusion between TEL and genes encoding proteins of various types. The most frequent 12p13 translocation is the t(12;21)(p13;q22), which recombines TEL with the AML1 gene on chromosome 21 and is frequently associated with deletion of the untranslocated TEL allele. Using antisera against different parts of TEL and against the AML1 proteins, we undertook Western blot and immunofluorescence analyses of leukemic samples with and without 12p13 abnormalities. In t(12;21) samples, TEL-AML1 was detected as several protein species in the nuclei, whereas the AML1-TEL protein, was inconsistently expressed. AML1 was found to be expressed but no normal TEL proteins were detected. A survey of the TEL proteins in a panel of human leukemic samples without t(12;21) revealed a variation in the ratio of TEL protein isoforms. We also analysed a leukemic cell line bearing a t(12;22)(p13;q11) that was found to affect the 5' untranslated (UT) region of TEL and to be associated with inactivation of the untranslocated TEL allele. No MN1-TEL fusion could be detected upon RT-PCR analysis, in contrast to the previously investigated t(12;22). Strikingly, extremely low levels of apparently normal TEL proteins, expressed from the translocated allele, were detected by Western blot analysis. These results suggest that the level of TEL expression can be important for leukemogenesis.
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PMID:Analysis of TEL proteins in human leukemias. 967 10

Chromosomal translocation often results in aberrant activation of the genes with oncogenic potential and, thus, plays an important role in leukemogenesis. We report a unique case of acute myelomonocytic leukemia carrying a rare reciprocal translocation, t(3;12)(q26;p13). This patient displayed typical clinical features of 3q21q26 syndrome such as abnormal thrombopoiesis and rapid disease progression. Blastic cells from the patient strongly expressed the EVI1 gene, which is located on 3q26 and is normally suppressed in bone marrow cells. Expression of the TEL gene, located on 12p13, was also observed, but fusion transcript between two genes was not found. No structural alterations of the EVI1 and TEL genes were detected by Southern blot and PCR analyses. We reviewed previous literature and found 10 other cases with t(3;12)(q26;p13). These patients comprise a unique disease group with features including dyshematopoiesis and poor prognosis. However, characteristics related to 3q21q26 syndrome were observed only in the present case. Further investigation is required to elucidate the molecular basis of this particular entity.
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PMID:A novel variant of acute myelomonocytic leukemia carrying t(3;12)(q26;p13) with characteristics of 3q21q26 syndrome. 969 9

To study constitutive Janus kinase signaling, chimeric proteins were generated between the pointed domain of the ets transcription factor TEL and the cytosolic tyrosine kinase Jak2. The effects of these proteins on interleukin-3 (IL-3)-dependent proliferation of the hematopoietic cell line, Ba/F3, were studied. Fusion of TEL to the functional kinase (JH1) domain of Jak2 resulted in conversion of Ba/F3 cells to factor-independence. Importantly, fusion of TEL to the Jak2 pseudokinase (JH2) domain or a kinase-inactive Jak2 JH1 domain had no effect on IL-3-dependent proliferation of Ba/F3 cells. Active TEL-Jak2 constructs (consisting of either Jak2 JH1 or Jak2 JH2+JH1 domain fusions) were constitutively tyrosine-phosphorylated but did not affect phosphorylation of endogeneous Jak1, Jak2, or Jak3. TEL-Jak2 activation resulted in the constitutive tyrosine phosphorylation of Stat1, Stat3, and Stat5 as determined by detection of phosphorylation using activation-specific antibodies and by binding of each protein to a preferential GAS sequence in electrophoretic mobility shift assays. Elucidation of signaling events downstream of TEL-Jak2 activation may provide insight into the mechanism of leukemogenesis mediated by this oncogenic fusion protein.
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PMID:Fusion of the ets transcription factor TEL to Jak2 results in constitutive Jak-Stat signaling. 1036 Nov 34

TEL-AML1 gene fusion derived by chromosomal translocation is a common acquired genetic lesion in pediatric cancer that is present in approximately 25% of B-cell precursor acute lymphoblastic leukemias, and recent evidence suggests that this recombination event may initiate leukemogenesis prenatally during fetal hemopoiesis. Analysis of the DNA sequence and structure surrounding the breakpoints may reveal clues to their formation. A long-distance inverse PCR strategy was used to amplify TEL-AML1 genomic fusion sequences from diagnostic DNA from nine patients. Breakpoints were scattered within the 14 kb of intronic DNA between exons 5 and 6 of TEL and in two putative cluster regions within AML1 intron 1. Fusion sequences exhibited characteristic signs of nonhomologous end joining, including microhomologies at the end points, and small deletions and duplications. DNA sequences near the breakpoints did not reveal any consistent characteristic signal sequences of the V(D)J recombinase, topoisomerase II consensus sites, or other sequence motifs associated with recombination. However, several translocations occurred near a repeat region of TEL that was found to be highly polymorphic. This region was cloned and found in nuclease sensitivity assays to exhibit paranemic structures, which may have contributed to DNA breakage or illegitimate recombination. The data are compatible with the possibility that TEL-AML1 translocations occur by nonhomologous recombination involving imprecise, constitutive repair processes following DNA double-strand breaks.
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PMID:Structure and possible mechanisms of TEL-AML1 gene fusions in childhood acute lymphoblastic leukemia. 1046 10

TEL is a gene frequently involved in specific chromosomal translocations in human leukemia and sarcoma that encodes a member of the ETS family of transcriptional regulators. TEL is unusual among other ETS proteins by its ability to self-associate in vivo, a property that is essential to the oncogenic activation of TEL-derived fusion proteins. We show here that TEL is a sequence-specific transcriptional repressor of ETS-binding site-driven transcription of model and natural promoters. Deletion of the oligomerization domain of TEL or its substitution by the homologous region of monomeric ETS1 impaired the ability of TEL to repress. In contrast, substitution of the oligomerization domain of TEL by unrelated oligomerization domains resulted in an active repressor, showing that the ability of TEL to repress depends on its ability to self-associate. The study of the properties of TEL fusions to the heterologous DNA binding domain of Gal4 identified two autonomous repression domains in TEL, distinct from its oligomerization domain, that are essential to the ability of TEL to repress ETS-binding site-containing promoters. These results have implications for the normal function of TEL, its relation to other ETS proteins, and its role in leukemogenesis.
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PMID:TEL is a sequence-specific transcriptional repressor. 1051 2

We describe a 41-year-old man with CD7-positive acute myeloid leukemia (AML-M0) with trilineage-myelodysplasia. Chromosome analysis of the bone marrow cells showed 46.XY.t(2;4;12) (p21;q12;p13). Cytological and clinical features of our case were quite similar to those of AML with t(4;12)(q11-12;p13). The karyotypic interpretation was confirmed by fluorescence in situ hybridization (FISH) by using the whole-chromosome painting probes specific for chromosomes 2, 4, and 12. FISH analysis with the use of the YAC 936e2 probe, which covers the TEL gene, did not show the split signal, suggesting that a gene other than TEL was involved in the leukemogenesis of the present case. Our case with AML with t(2;4;12)(p21;q12;p13) appears to be the first case of a variant type of AML with t(4;12) (q11-12;p13).
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PMID:A new translocation, t(2;4;12)(p21;q12;p13), in CD7-positive acute myeloid leukemia: a variant form of t(4;12). 1054 63

The TEL/AML1 fusion gene occurs in childhood B-cell acute lymphoblastic leukemia (ALL) as a result of the translocation of human chromosome 12;21. Using reporter gene assays, we have functionally characterized TEL, AML1 and TEL/AML1 fusion proteins in the regulation of the human CR1 gene. Analysis of transcription activities showed that AML1 increased the CR1 promoter activity and that TEL repressed the basal activity of the promoter. Increased activities of the CR1 promoter by AML1 protein were reduced by the TEL protein in a concentration-dependent manner. When TEL/AML1 and AML1 proteins are present in cells at the same time, the TEL/AML1 protein inhibits the transactivation activities of AML1 protein on the human CR1 promoter even though TEL/AML1 retains the transactivation domain of AML1. A mutation analysis of the human CR1 promoter revealed that the binding sites for TEL and AML1 are necessary for the action of TEL and TEL/AML1, respectively. Thus, production of the TEL/AML1 protein by translocation of human chromosome 12;21 may contribute to leukemogenesis by the specific inhibition of AML1-dependent activation of myeloid promoters.
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PMID:Functional characterization of TEL/AML1 fusion protein in the regulation of human CR1 gene promoter. 1059 47

The AML1 and CBFbeta subunits of core binding factor (CBF) are involved in several chromosomal abnormalities frequently associated with acute leukemias. As a result, the CBFbeta-SMMHC, AML1-ETO and AML1-MDS1/EVI1 fusion proteins are expressed in subsets of acute myeloid leukemia, and TEL-AML1 is expressed in B-lineage acute lymphocytic leukemia. These CBF oncoproteins likely contribute to leukemogenesis in part by inhibiting endogenous CBF. As a result they are expected to inhibit differentiation and perhaps apoptosis. In addition, the domains unique to each fusion protein may also contribute to leukemogenesis via unique mechanisms.
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PMID:Leukemogenesis by CBF oncoproteins. 1060 13

Childhood leukemia is the commonest form of childhood cancer and represents clonal proliferation of transformed hemopoietic cells as a result of genetic changes. Molecular characterization of these changes, in particular chromosomal translocations, has yielded a wealth of information on the mechanisms of leukemogenesis. These findings have also allowed the development of sensitive assays for the identification of underlying molecular defects, which is applicable to disease diagnosis and to monitor response to treatment. Genetic alterations in childhood leukemia are powerful prognostic indicators. TEL-AML1 fusion and hyperdiploidy >50 chromosomes are associated with a good prognosis in childhood acute lymphoblastic leukemia, whereas BCR-ABL fusion and MLL rearrangements are associated with a poor prognosis. Hence cytogenetic and molecular genetic classification of childhood leukemia will significantly improve the ability of clinicians to predict therapeutic response and prognosis, which paves the way for risk stratification based on clinical and genetic features. Finally, deciphering of genetic lesions in leukemia has allowed elucidation of the molecular basis of current treatment, as typified by the success of all-trans retinoic treatment in acute promyelocytic leukemia, and has identified targets for novel therapeutic approaches. It is envisaged that efforts in characterization of molecular defects in childhood leukemia will ultimately be translated into better clinical outcome for patients.
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PMID:Cytogenetics and molecular genetics of childhood leukemia. 1064 Oct 30

The t(12;21)(p13;q22) chromosomal translocation is the most frequent illegitimate gene recombination in a pediatric cancer and occurs in approximately 25% of common acute lymphoblastic leukemia (cALL) cases. This rearrangement results in the in frame fusion of the 5'-region of the ETS-related gene, TEL (ETV6), to almost the entire acute myeloid leukemia 1 (AML1) (also called CBFA2 or PEBP2AB1) locus and expression of the TEL-AML1 chimeric protein. Although AML1 stimulates transcription, TEL-AML1 functions as a repressor of some AML1 target genes. In contrast to the wild type AML1 protein, both TEL and TEL-AML1 interact with N-CoR, a component of the nuclear receptor corepressor complex with histone deacetylase activity. The interaction between TEL and N-CoR requires the central region of TEL, which is retained in TEL-AML1, and TEL lacking this domain is impaired in transcriptional repression. Taken together, our results suggest that TEL-AML1 may contribute to leukemogenesis by recruiting N-CoR to AML1 target genes and thus imposing an altered pattern of their expression.
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PMID:Recruitment of the nuclear receptor corepressor N-CoR by the TEL moiety of the childhood leukemia-associated TEL-AML1 oncoprotein. 1100 11


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