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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The TEL and AML1 genes are common targets of chromosomal translocations in hematopoietic malignancies. The TEL-AML1 fusion gene, created by the t(12;21), is the most common genetic alteration in childhood acute lymphoblastic leukemia and is associated with a favorable outcome. This review summarizes the roles of the TEL and AML1 proteins in hematopoiesis, the potential transforming mechanisms of TEL fusion proteins, and the clinical significance of the TEL-AML1 fusion.
Leukemia 1999 Jan
PMID:The role of TEL fusion genes in pediatric leukemias. 1004 61

The accurate identification of chromosomal abnormalities in patients with leukemia is essential for diagnosis and treatment assignment. Recent technical improvements in the detection of such aberrations have demonstrated that the previously unrecognized chromosomal translocation t(12;21) is the most prevalent structural aberration in childhood acute lymphoblastic leukemia. Both genes involved, translocation ets like gene (or ETV6) on chromosome 12 and acute myeloid leukemia 1 gene (or CBF alpha) on chromosome 21 had been identified for several years previously, which facilitated the rapid development of molecular diagnostic assays and their implementation in therapy trials. Although first described less than four years ago, the TEL/AML1 story is an excellent example of how close collaboration between physicians and molecular biologists is mandatory for achieving general insights into the molecular pathogenesis of leukemia and for further improvements in diagnosis and in monitoring response to chemotherapy.
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PMID:Biology and clinical significance of the TEL/AML1 rearrangement. 1008 81

The nonrandomness of chromosomal abnormalities of hematopoietic malignancies, which has been established twenty years ago, has evidenced a more or less close relationship between some structural chromosomal abnormalities and leukemia subtypes. The same relation was, then, shown between gene and chromosome rearrangements. It becomes now obvious that genes involved in malignant proliferations may rearrange several different partner genes, as for instance the genes MLL, localised to chromosome band 11q23, and ETV6/TEL to 12p13. The study of these rearrangements is of particular importance in order to improve our knowledge of the functions of rearranged genes as well as their normal counterparts, and to analyse mechanisms favoring the occurrence of chromosomal rearrangements in malignancies.
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PMID:[Promiscuous genes and chromosomal rearrangements of hematopoietic malignancies]. 1021 4

The t(12;21) is the commonest recurrent translocation in childhood acute lymphoblastic leukaemia (ALL), the presence of which has been suggested to be a good prognostic feature. We have studied 22 childhood cases of B-precursor ALL with this rearrangement, and have found no significant differences in event-free survival between these and a control group of patients with similar phenotypes. Using a variety of cytogenetic and molecular techniques, we have confirmed a strong association with co-expression of myeloid markers, frequent deletions of the short-arm of the untranslocated chromosome 12 homologue and duplication of the derivative chromosome 21. Intragenic deletion of the untranslocated ETV6 gene in 3/12 informative patients points to the likelihood of this gene being a target for deletion.
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PMID:An investigation of the t(12;21) rearrangement in children with B-precursor acute lymphoblastic leukaemia using cytogenetic and molecular methods. 1035 32

The E-26 transforming specific (ETS)-related gene TEL, also known as ETV6, is involved in a large number of chromosomal rearrangements associated with leukemia and congenital fibrosarcoma. The encoded protein contains two functional domains: a helix-loop-helix (HLH) domain (also known as pointed domain) located at the N terminus and a DNA-binding domain located at the C terminus. The HLH domain is involved in protein-protein interaction with itself and other members of the ETS family of transcription factors such as FLI1. TEL is a transcription factor, and we and others have shown that it is a repressor of gene expression. To understand further the role of TEL in the cell, we have used an in vivo interaction system to identify proteins that interact with TEL. We show that a protein, UBC9, interacts specifically with TEL in vitro and in vivo. UBC9 is a member of the family of ubiquitin-conjugating enzymes. These enzymes usually are involved in proteosome-mediated degradation; however, our data suggest that interaction of TEL with UBC9 does not lead to TEL degradation. Our studies show that UBC9 binds to TEL exclusively through the HLH domain of TEL. We also show that TEL expressed as fusion to the DNA-binding domain of Gal4 completely represses a Gal4-responsive promoter, but that the coexpression of UBC9 in the same system restores the activity of the promoter. Targeted point mutation of conserved amino acids in UBC9 essential for enzymatic ubiquitination of proteins does not affect interaction nor transcriptional activity. Based on our data, we conclude that UBC9 physically interacts with TEL through the HLH domain and that the interaction leads to modulation of the transcription activity of TEL.
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PMID:Modulation of TEL transcription activity by interaction with the ubiquitin-conjugating enzyme UBC9. 1037 38

Of 29 infants with acute myeloid leukemia (AML), 14 (48%) had various 11q23 translocations. MLL rearrangements were examined in 21 of the 29 patients, and 11 (52%) showed the rearrangements. 11q23 translocations and/or MLL rearrangements were found in 17 (58%) of the 29 patients. While all but one of the 17 patients with 11q23/MLL rearrangements had M4 or M5 type of the FAB classification, the 12 patients without such rearrangements had various FAB types, including M2, M4, M4EO, M6 and M7. Of the 12 patients with other chromosome abnormalities or normal karyotypes, two had inv(16) ort(16;16), one had t(1;22)(p13;q13), and two had a novel translocation, t(7;12)(q32;p13). The breakpoint on 12p of the t(7;12) was assigned to intron 1 or the region just upstream of exon 1 of the TEL/ETV6 gene by fluorescence in situ hybridization. The event-free survival at 5 years for the 17 patients with 11q23/MLL rearrangements was 42.2%, and that for the 12 patients without such rearrangements was 31.3% (P = 0.5544). 11q231MLL rearrangements have been frequently reported and a poor prognosis in infant acute lymphoblastic leukemia implied. Our study showed that while 11q23/MLL rearrangements were also common in infant AML, AML infants with such rearrangements had a clinical outcome similar to that of AML infants without such rearrangements.
Leukemia 1999 Jul
PMID:Chromosome abnormalities and MLL rearrangements in acute myeloid leukemia of infants. 1040 Apr 16

We report a pair of identical twins with concordant acute lymphoblastic leukemia (ALL). Unusually, their diagnoses were spaced 9 years apart at ages 5 and 14. Leukemic cells in both twins had a TEL-AML1 rearrangement, which was characterized at the DNA level by an adaptation of a long distance polymerase chain reaction (PCR) method. The genomic fusion sequence was identical in the two leukemias, indicative of a single cell origin in one fetus, in utero. At the time twin 1 was diagnosed (aged 5 years), the bone marrow of twin 2 was hematologically normal. However, retrospective scrutiny of the DNA from an archived slide with clonotypic TEL-AML1 primers showed that the presumptive preleukemic clone was present and disseminated 9 years before a clinical diagnosis. These data provide novel insight into the natural history of childhood leukemia and suggest that consequent to a prenatal initiation of a leukemic clone, most probably by TEL-AML fusion itself, the latency of ALL can be both extremely variable and protracted. This, in turn, is likely to reflect the timing of critical secondary events.
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PMID:Protracted and variable latency of acute lymphoblastic leukemia after TEL-AML1 gene fusion in utero. 1041 98

The Janus kinase family of proteins, with four mammalian members (JAK1, JAK2, JAK3 and TYK2), plays an essential role in the signal transduction pathway from non-catalytic cytokine receptors to the nucleus. We recently reported the involvement of ETV6-JAK2 fusion genes in the development of leukemia of both lymphoid and myeloid origin. Dominant missense mutations of hopscotch, a Drosophila JAK homologue, causing leukemia-like defects were described. One of these mutations affected a conserved residue of the kinase- like JH2 domain and the introduction of this mutation in murine Jak2 resulted in the constitutional activation of its kinase activity. In order to further analyze its role in leukemogenesis, we cloned human JAK2 and determined its genomic organization. Twenty-four exons spanning a region of approximately 150 kb were identified. A mutation analysis of the exons 13 to 19, encoding the kinase-like JH2 domain failed to detect activating mutations in leukemia samples, suggesting that this is a rare event in human leukemia.
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PMID:Genomic organization of human JAK2 and mutation analysis of its JH2-domain in leukemia. 1044 13

Rearrangements and fusion of the MLL gene with various alternative partner genes occur in approximately 80% of infant leukemias and are acquired during fetal hemopoiesis in utero. Similar MLL gene recombinants also occur in topoisomerase II-inhibiting drug-induced leukemias. These data have led to the suggestion that some infant leukemia may arise via transplacental fetal exposures during pregnancy to substances that form cleavable complexes with topoisomerase II and induce illegitimate recombination of the MLL gene. A structural feature shared by many topoisomerase II-inhibiting drugs and other chemicals is the quinone moiety. We assayed, by PCR-RFLP, for a polymorphism in an enzyme that detoxifies quinones, NAD(P)H:quinone oxidoreductase (NQO1), in a series (n = 36) of infant leukemias with MLL rearrangements versus unselected cord blood controls (n = 100). MLL-rearranged leukemias were more likely to have genotypes with low NQO1 function (heterozygous CT or homozygous TT at nucleotide 609) than controls (odds ratio, 2.5; P = 0.015). In contrast, no significant allele bias was seen in other groups of pediatric leukemias with TEL-AML1 fusions (n = 50) or hyperdiploidy (n = 29). In the subset of infant leukemias that had MLL-AF4 fusion genes (n = 21), the bias increase in low or null function NQO1 genotypes was more pronounced (odds ratio, 8.12; P = 0.00013). These data support the idea of a novel causal mechanism in infant leukemia involving genotoxic exposure in utero and modulation of impact on a selective target gene by an inherited allele encoding a rate-limiting step in a carcinogen detoxification pathway.
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PMID:A lack of a functional NAD(P)H:quinone oxidoreductase allele is selectively associated with pediatric leukemias that have MLL fusions. United Kingdom Childhood Cancer Study Investigators. 1046 13

The ETV6 gene (also known as TEL) is the main target of chromosomal translocations affecting chromosome band 12p13. The rearrangements fuse ETV6 to a wide variety of partner genes in both myeloid and lymphoid malignancies. We report here 4 new cases of acute myeloid leukemia (AML) with very immature myeloblasts (French-American-British [FAB]-M0) and with a t(4;12)(q11-q12;p13). In all cases, ETV6 was found recombined to a new gene, homologous to the mouse Brx gene. The gene was named BTL (Brx-like Translocated in Leukemia). Reverse transcriptase-polymerase chain reaction (RT-PCR) experiments indicate that the expression of the BTL-ETV6 transcript, but not of the reciprocal ETV6-BTL transcript, is a common finding in these leukemias. In contrast to the majority of other ETV6 fusions, both the complete helix-loop-helix (HLH) and ETS DNA binding domains of ETV6 are present in the predicted BTL-ETV6 fusion protein, and the chimeric gene is transcribed from the BTL promoter.
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PMID:Fusion of a novel gene, BTL, to ETV6 in acute myeloid leukemias with a t(4;12)(q11-q12;p13). 1047 9


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