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)

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.
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PMID:Chromosome abnormalities and MLL rearrangements in acute myeloid leukemia of infants. 1040 Apr 16

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

Certain chromosome abnormalities, especially translocations, are specifically associated with particular subtypes of leukemia, lymphoma, and sarcomas. This review describes the translocations involving the AML1(CBFA2) gene on 21q22, the MLL gene on 11q23, and the TEL(ETV6) gene on 12p13. Abnormalities of these genes account for a large proportion of patients with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Cloning of translocation breakpoints results in unique diagnostic tools for fluorescence in situ hybridization (FISH) and molecular analysis of leukemic cells. Recent advances in understanding the alterations in the function of the fusion genes as compared with normal genes provide insights regarding new therapeutic strategies, which should lead to improved clinical responses with less toxicity.
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PMID:The role of chromosome translocations in leukemogenesis. 1059 55

Prospective studies on the detection of minimal residual disease (MRD) in acute leukemia patients have shown that large-scale MRD studies are feasible and that clinically relevant MRD-based risk group classification can be achieved and can now be used for designing new treatment protocols. However, multicenter international treatment protocols with MRD-based stratification of treatment need careful standardization and quality control of the MRD techniques. This was the aim of the European BIOMED-1 Concerted Action 'Investigation of minimal residual disease in acute leukemia: international standardization and clinical evaluation' with participants of 14 laboratories in eight European countries (ES, NL, PT, IT, DE, FR, SE and AT). Standardization and quality control was performed for the three main types of MRD techniques, ie flow cytometric immunophenotyping, PCR analysis of antigen receptor genes, and RT-PCR analysis of well-defined chromosomal aberrations. This study focussed on the latter MRD technique. A total of nine well-defined chromosome aberrations with fusion gene transcripts were selected: t(1;19) with E2A-PBX1, t(4;11) with MLL-AF4, t(8;21) with AML1-ETO, t(9;22) with BCR-ABL p190 and BCR-ABL p210, t(12;21) with TEL-AML1, t(15;17) with PML-RARA, inv (16) with CBFB-MYH11, and microdeletion 1p32 with SIL-TAL1. PCR primers were designed according to predefined criteria for single PCR (external primers A <--> B) and nested PCR (internal primers C <--> D) as well as for 'shifted' PCR with a primer upstream (E5' primer) or downstream (E3' primer) of the external A <--> B primers. The 'shifted' E primers were designed for performing an independent PCR together with one of the internal primers for confirmation (or exclusion) of positive results. Various local RT and PCR protocols were compared and subsequently a common protocol was designed, tested and adapted, resulting in a standardized RT-PCR protocol. After initial testing (with adaptations whenever necessary) and approval by two or three laboratories, the primers were tested by all participating laboratories, using 17 cell lines and patient samples as positive controls. This testing included comparison with local protocols and primers as well as sensitivity testing via dilution experiments. The collaborative efforts resulted in standardized primer sets with a minimal target sensitivity of 10-2 for virtually all single PCR analyses, whereas the nested PCR analyses generally reached the minimal target sensitivity of 10-4. The standardized RT-PCR protocol and primer sets can now be used for molecular classification of acute leukemia at diagnosis and for MRD detection during follow-up to evaluate treatment effectiveness.
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PMID:Standardized RT-PCR analysis of fusion gene transcripts from chromosome aberrations in acute leukemia for detection of minimal residual disease. Report of the BIOMED-1 Concerted Action: investigation of minimal residual disease in acute leukemia. 1060 11

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

As the overall long-term event-free survival rate in children with acute lymphoblastic leukemia approaches 80%, emphasis is being placed on risk-directed therapy so that patients are neither overtreated nor undertreated. It has become apparent that a risk assignment system based on primary genetic abnormalities is inadequate by itself. For example, leukemias with the MLL-AF4 or BCR-ABL fusion gene are, in fact, heterogeneous diseases. Many require allogeneic hematopoietic stem-cell transplantation; some, if the patient is of favorable age and has a low presenting leukocyte count, can be cured with chemotherapy alone. Measurement of early responses to therapy and extent of minimal residual disease can greatly improve the accuracy of risk assessment. Consideration of the variable effects of therapy on the prognostic significance of specific genetic abnormalities is also important. Therefore, TEL-AML1 fusion confers a favorable prognosis in some protocols of chemotherapy but not in others. Studies to identify genetic polymorphisms with pharmacokinetic and pharmacodynamic significance promise to guide further refinement of treatment strategies. This will allow maximization of anticancer effects without induction of unacceptable toxicity in individual patients.
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PMID:Acute lymphoblastic leukemia in children. 1068 23

Acute lymphoblastic leukemia (ALL) is the most common cancer in children and is among the most curable of the pediatric malignancies. Many clinical, biological, genetic, and molecular features have been identified as having prognostic significance in the outcome of patients with ALL. The standard features are age and WBC at diagnosis, with infants (less than one year), adolescents (greater than nine years), and children with WBC above 50,000/microl being at higher risk. Certain chromosomal abnormalities are also strong predictors; in particular, the Philadelphia chromosome and MLL gene rearrangements (especially in infants) are adverse features, while TEL-AML1 is favorable. It is important to note, however, that even the most important known predictors explain only a small proportion of the variability in outcome. These features are currently used to tailor the intensity of treatment so that the toxicity of treatment can be minimized and cure rates can continue to improve. This article reviews time-honored prognostic features, recent advances, and future directions in this field.
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PMID:The role of prognostic features in the treatment of childhood acute lymphoblastic leukemia. 1096

B-cell precursor acute lymphoblastic leukemias (BCP-ALLs) are increasingly treated on risk-adapted protocols based on presenting clinical and biological features. Residual molecular positivity of clonal immunoglobulin (IG) and T-cell receptor (TCR) rearrangements allows detection of patients at an increased risk of relapse. If these rearrangements are to be used for universal follow-up, it is important to determine the extent to which they are informative in different BCP-ALL subsets. We show that IGH V-D-J rearrangements occur in 89% of 163 BCP-ALL, with no significant variation according to age or genotype (BCR-ABL, TEL-AML1, MLL-AF4, and E2A-PBX1). In contrast, TCRG rearrangements, which occur in 60% of patients overall, are frequent in BCR-ABL and TEL-AML1, are less so in MLL-AF4, and are virtually absent in infants aged predominantly from 1 to 2 years and in E2A-PBX1 ALLs. Incidence of the predominant TCRD Vdelta2-Ddelta3 rearrangement decreases with age but is independent of genotype. These differences are not due to differential recombination activating gene activity, nor can they be explained adequately by stage of maturation arrest. Analysis of MLL-AF4 BCP-ALL is in keeping with transformation of a precursor at an early stage of ontogenic development, despite the adult onset of the cases analyzed. We postulate that the complete absence of TCRG rearrangement in E2A-PBX1 cases may result from deregulated E2A function. These data also have practical consequences for the use of TCR clonality for the molecular follow-up of BCP-ALL.
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PMID:The incidence of clonal T-cell receptor rearrangements in B-cell precursor acute lymphoblastic leukemia varies with age and genotype. 1097 74

Somatically acquired genetic alterations play an important role in the pathogenesis of acute lymphoblastic leukemia. The molecular analysis of these alterations has increased our understanding of the mechanisms of leukemogenesis. In addition, this information has led to improvements in our abilities to predict treatment response and to deliver the optimal intensity of treatment to individual patients. For example, the prognosis for patients with acute lymphoblastic leukemia whose leukemic cells express the TEL-AML1 fusion is favorable when they are treated on modem chemotherapy protocols, whereas patients whose leukemic lymphoblasts contain the MLL-AF4 or the BCR-ABL fusion sometimes require allogeneic hematopoietic stem cell transplantation for cure. Molecular techniques are also used to detect minimal residual disease and genetic polymorphisms that are important in optimizing drug therapy.
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PMID:Molecular diagnostics in the treatment of childhood acute lymphoblastic leukemia. 1103 50

Since 1994, chimeric gene test for major-BCR/ABL, minor-BCR/ABL, AML1/MTG8, PML/RARa, DEK/CAN, CBFb/MYH11, MLL/LTG9, E2A/PBX1, TEL/AML1, and MLL/LTG4 by reverse transcription-nested-polymerase chain reaction (RT-nested-PCR) have been routinely performed in our laboratory. The frequently requested tests were those for major-BCR/ABL, minor-BCR/ABL, AML1/MTG8, PML1/RARa, and TEL/AML1 chimeric genes, being the test for major-BCR/ABL the most frequent one, accounting for more than 50% of the total orders. By the high sensitivity for minimal residual disease(MRD) detection, these methods are extremely useful for the therapeutic control of chemotherapy and bone marrow transplantation, as well as for prediction of prognosis. However, in the most cases a well-controlled monitoring could not be obtained, due to the 6-months interval between the tests, the minimal interval allowed by the insurance. The following points should be carefully observed. (1) The setting site of the primer can affect the sensitivity and the specificity of the test; (2) For the detection of chimeric genes with multiple translocation breakpoints, a genetic DNA sequencing is necessary to confirm them; (3) In patients receiving chemotherapy or bone marrow transplantation, that show extremely low blood cell counts, false-negative tests dependent on the quality of the extracted RNA and the low volume of DNA, should be avoided by careful managements. For improvements of the MRD detection tests, the quantification of the expression levels of chimeric gene and WT1 mRNA is necessary.
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PMID:[The genetic diagnosis of hematopoietic malignancy by polymerase chain reaction method]. 1106 93


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