The role of TEL fusion genes in pediatric leukemias

Rubnitz, Jeffrey E.; Pui, Ching‐Hon; Downing, James R.

doi:10.1038/sj.leu.2401258

Cited by 114 publications

(82 citation statements)

References 45 publications

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“…5,6 The ETV6/AML1 fusion transcript is likely to be important for leukemogenesis. 7 Recent reports 1,3,4,8 have shown that this gene rearrangement is associated with a clinically defined subgroup of precursor-B-ALL affecting children with ages from 1 to 12 years who show non-hyperdiploid leukemic lymphoblasts and do not display hyperleukocytosis. Moreover, the presence of the ETV6/AML1 transcript has been found to be associated with a good prognosis since patients with t(12;21) translocation, as compared with other patients, display a higher response rate to chemotherapy.…”

Section: Introductionmentioning

confidence: 98%

“…[1][2][3][4] The molecular consequence of the t(12;21)(p13;q22) translocation is the fusion of two known genes named ETV6, mapped to 12p13, and AML1, located at 21q22. This translocation results in the transcription of a chimeric protein which consists of the helix-loop-helix domain of ETV6 and the entire AML1 gene, including both its DNA binding and transactivation domains.…”

Section: Introductionmentioning

confidence: 99%

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Quantitative multiparametric immunophenotyping in acute lymphoblastic leukemia: correlation with specific genotype. I. ETV6/AML1 ALLs identification

et al. 2000

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The t(12;21)(p13;q22) fusion gene is the most frequent genetic lesion described in precursor B cell acute lymphoblastic leukemia (ALL) of childhood occurring in a quarter of cases. This gene rearrangement is associated with a good outcome presenting a high response rate to chemotherapy. In spite of its potential clinical relevance, the t(12;21) translocation usually goes undetected with conventional cytogenetic procedures. In the present study we utilized an objective flow cytometric approach (multiparametric quantitative analysis) for the phenotypic characterization of this type of ALL. We studied a total of 74 precursor B-ALL children, including 21 t(12;21) + and 53 t(12;21) − cases. Our results show that the t(12;21)(p13;q22) + ALLs display a higher intensity of CD10 (P = 0.0016) and HLADR (P = 0.005) expression together with lower levels of the CD20 (P = 0.01), CD45 (P = 0.01), CD135 (P = 0.003) and CD34 (P = 0.03) antigens as compared to the t(12;21) − cases. Moreover, as regards CD34 expression, we observed a more heterogeneous antigen expression within individual patients with higher coefficients of variation (median of 202 vs 88, P = 0.0001). A multivariate analysis disclosed that with the immunophenotypic approach used identification of t(12;21) + cases can be achieved with a sensitivity of 86% and a specificity of 100%. We conclude that childhood precursor B-ALL carrying the t(12;21) translocation display characteristic phenotypic features which could provide a rapid, simple, sensitive and specific screening method to select for those cases that should undergo confirmatory molecular analysis. Leukemia (2000) 14, 1225-1231.

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Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Quantitative multiparametric immunophenotyping in acute lymphoblastic leukemia: correlation with specific genotype. I. ETV6/AML1 ALLs identification

et al. 2000

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“…Most of these abnormalities induce the expression of fusion proteins between TEL sequences and amino-acid sequences encoded by the partner gene (Rubnitz et al, 1999;Salomon-Nguyen et al, 2000 and references therein). The largest class of TEL's partner genes encodes protein tyrosine kinases whose catalytic domains are fused to the amino-terminal part of TEL.…”

Section: Introductionmentioning

confidence: 99%

Functional analyses of the TEL-ARNT fusion protein underscores a role for oxygen tension in hematopoietic cellular differentiation

et al. 2006

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The transcription factor hypoxia inducible factor 1 (HIF1), an HIF1a-aryl hydrocarbon receptor nuclear translocator (ARNT) dimeric factor, is essential to the cellular response to hypoxia. We described a t(1;12)(q21;p13) chromosomal translocation in human acute myeloblastic leukemia that involves the translocated Ets leukemia (TEL/ETV6) and the ARNT genes and results in the expression of a TEL-ARNT fusion protein.Functional studies show that TEL-ARNT interacts with HIF1a and the complex binds to consensus hypoxia response element. In low oxygen tension conditions, the HIF1a/TEL-ARNT complex does not activate transcription but exerts a dominant-negative effect on normal HIF1 activity. Differentiation of normal human CD34 þ progenitors cells along all the erythrocytic, megakaryocytic and granulocytic pathways was accelerated in low versus high oxygen tension conditions. Murine 32Dcl3 myeloid cells also show accelerated granulocytic differentiation in low oxygen tension in response to granulocyte colony-stimulating factor. Interestingly, stable expression of the TEL-ARNT in 32Dcl3 subclones resulted in impaired HIF1-mediated transcriptional response and inhibition of differentiation enhancement in hypoxic conditions. Taken together, our results underscore the role of oxygen tension in the modulation of normal hematopoietic differentiation, whose targeting can participate in human malignancies.

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“…The CBFA2 gene translocations include the t(8;21) CBFA2/ETO, associated with *15% acute myeloid leukaemia, the t(3;21) observed in some cases of chronic myeloid leukaemia and more rarely in therapy-related leukaemias and myelodysplasias (reviewed in Nucifora et al, 1995) and the t(12;21) TEL/CBFA2 translocation frequently found in both childhood and adult pre-B acute lymphocytic leukaemia (reviewed in Rubnitz et al, 1999). The CBFB subunit is also disrupted by both inversion and gene deletion in acute myeloid leukaemia (Liu et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

A full-length Cbfa1 gene product perturbs T-cell development and promotes lymphomagenesis in synergy with MYC

et al. 1999

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The role of TEL fusion genes in pediatric leukemias

Cited by 114 publications

References 45 publications

Quantitative multiparametric immunophenotyping in acute lymphoblastic leukemia: correlation with specific genotype. I. ETV6/AML1 ALLs identification

Quantitative multiparametric immunophenotyping in acute lymphoblastic leukemia: correlation with specific genotype. I. ETV6/AML1 ALLs identification

Functional analyses of the TEL-ARNT fusion protein underscores a role for oxygen tension in hematopoietic cellular differentiation

A full-length Cbfa1 gene product perturbs T-cell development and promotes lymphomagenesis in synergy with MYC

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