Molecular analysis of chromosomal breakpoints in three examples of chromosomal translocation involving the TEL gene

Romana, SP; Poirel, Hélène; Valle, V. Della; Mauchauffé, M; Coniat, Maryvonne Busson‐Le; Berger, Roland; Bernard, O.

doi:10.1038/sj.leu.2401564

Cited by 17 publications

(15 citation statements)

References 10 publications

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“…There might not be an exclusive second genetic 'hit', but at diagnosis most cases of ALL with TEL-AML1 fusions have deletion of the nonrearranged or normal TEL allele. Deletions are subclonal to TEL-AML1 fusions (Romana et al, 1996) and are distinct in their genomic boundaries in twins (Maia et al, 2001), and in relapse versus diagnostic samples from the same individuals . TEL deletions are therefore likely to be postnatal secondary events, albeit a common and integral component of the molecular pathogenesis of cALL .…”

Section: An Initiating Role For Tel-aml1 In Pathogenesis Of Childhoodmentioning

confidence: 99%

Role of the TEL-AML1 fusion gene in the molecular pathogenesis of childhood acute lymphoblastic leukaemia

2004

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Balanced chromosomal translocations are frequently associated with haematopoietic neoplasms and often involve genes that encode transcription factors, which play critical roles in normal haematopoiesis. Fusion oncoproteins that arise from chimeric genes generated by such translocations are usually stable and consistent molecular markers for a given disease subtype and contribute to the leukaemogenic processes. The t(12;21)(p13;q22) chromosomal translocation is the most frequent illegitimate gene recombination in paediatric cancer, occurring in approximately 25% of common (c) B-cell precursor acute lymphoblastic leukaemia (cALL) cases. The rearrangement results in the in-frame fusion of the 5 0 region of the ETS-related gene, TEL (ETV6), to almost the entire AML1 (RUNX1) locus and is associated with favourable prognosis following conventional therapeutic strategies. We discuss here the prenatal origins of the TEL/AML1 translocation as an initiating mutation, the role of TEL-AML1 in cellular transformation and the molecular mechanisms by which the chimeric protein imposes altered patterns of gene expression.

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Section: An Initiating Role For Tel-aml1 In Pathogenesis Of Childhoodmentioning

confidence: 99%

Role of the TEL-AML1 fusion gene in the molecular pathogenesis of childhood acute lymphoblastic leukaemia

2004

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“…The t(12;21) is found in approximately 25% of pediatric B-cell acute leukemia and it creates a fusion protein between the N-terminus of TEL (ETV 6) (residues 1 ± 336) and the AML-1 (Runx-1) transcription factor (residues 21 ± 480). In most of the leukemias containing the t(12;21), the other allele of TEL is deleted, indicating that loss of TEL function contributes to leukemogenesis (Raynaud et al, 1996;Romana et al, 1996;Stegmaier et al, 1995). Loss of at least one TEL allele is also observed in various solid tumors including breast and ovarian cancers, suggesting that TEL plays an important role in tumorigenesis (Hatta et al, 1997;Spirin et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

TEL contacts multiple co-repressors and specifically associates with histone deacetylase-3

Wang

Hiebert

2001

Oncogene

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TEL (Translocation ± ETS ± Leukemia or ETV 6) is disrupted by multiple chromosomal translocations in acute leukemia. The loss of heterozygosity at the TEL locus in leukemias and the hemizygous deletion of TEL that is observed in various tumors, suggests that TEL is a tumor suppressor. Overexpression of TEL alters cellular morphology and represses the expression of the matrix metalloproteinase stromelysin-1. Based on these studies, deletion analysis was used to de®ne the minimal repression domains of TEL. TEL-mediated repression required both the N-terminal pointed domain and a central region composed of amino acids 268 ± 303. The mSin3A and N-CoR corepressors bind to the pointed domain and the central repression domain of TEL, respectively. Unexpectedly, histone deacetylase-3, but not other histone deacetylases, also associates with the central region of TEL. Histone deacetylase-3 interacts with a TEL mutant that cannot bind N-CoR, suggesting that this is a direct interaction with TEL. In addition, histone H3 was under-acetylated near the TEL-binding sites in the endogenous stromelysin-1 promoter when TEL was expressed. Furthermore, trichostatin A, a potent histone deacetylase inhibitor, impaired TELdependent repression of the stromelysin-1 promoter. Finally, while TEL-expression induced cellular aggregation of Ras-transformed cells, Trichostatin A reversed the TEL-induced cellular aggregation phenotype. Thus, the cumulative data suggests that histone deacetylase-3 activity is required for the transcriptional functions of TEL. Oncogene (2001) 20, 3716 ± 3725.

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“…[18][19][20] The most common rearrangement in childhood leukemias is t(12;21)TEL-AML1, and we and others have noted structural features of the introns that may contribute to genomic breakage and refusion, including unstable repeat sequences and signs of non-homologous end joining repair. 14,[21][22][23][24] T(8;21) (AML1-ETO) is a common recurrent translocation (ෂ12% overall) in both childhood and adult AML. This translocation is primarily a de novo, or idiopathic event, by the lack of identified causal exposure in most of the cases.…”

Section: Introductionmentioning

confidence: 99%

Molecular characterization of genomic AML1-ETO fusions in childhood leukemia

et al. 2001

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T(8;21) AML1(CBFA2)-ETO(MTG8)is the most common chromosomal translocation in acute myeloid leukemia (AML) in both children and adults. We sought to understand the structure and gain insight into the fusion process between AML1 and ETO by sequencing genomic fusions in 17 primary childhood AMLs and two cell lines with t(8;21). Reciprocal translocations were sequenced for seven of the 19 samples. We assumed a null hypothesis that the translocation breakpoints would be evenly distributed along the intronic breakpoint cluster regions. Testing for multimodality via smoothed bootstrap statistical methods suggested, however, the presence of two separate cluster regions within both the AML1 and ETO breakpoint cluster regions. ETO breakpoints were predominantly located in intron 1B in a defined cluster 5Ј of exon 1A (scan statistic P value = 0.00001). All patients with available RNA expressed an AML1-ETO mRNA fusion between exon 5 of AML1 and exon 2 of ETO. Since the structural restraints for the fusion protein of AML1-ETO exclude exon 1A, we reason that ETO intron 1B harbors a structural feature with propensity for breakage and/or recombination. Chromosomal breakpoints displayed evidence of fusion by a non-homologous end joining process, with microhomologies and nontemplate nucleotides at some fusion junctions. Breakpoints in general displayed similar complexity of duplications, deletions, and insertions to other common pediatric leukemia translocations (TEL-AML1, MLL-AF4, PML-RARA, CBFB-MYH11) that we and others have analyzed. Leukemia (2001Leukemia ( ) 15, 1906Leukemia ( -1913

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Molecular analysis of chromosomal breakpoints in three examples of chromosomal translocation involving the TEL gene

Cited by 17 publications

References 10 publications

Role of the TEL-AML1 fusion gene in the molecular pathogenesis of childhood acute lymphoblastic leukaemia

Role of the TEL-AML1 fusion gene in the molecular pathogenesis of childhood acute lymphoblastic leukaemia

TEL contacts multiple co-repressors and specifically associates with histone deacetylase-3

Molecular characterization of genomic AML1-ETO fusions in childhood leukemia

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