Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent advances in cytogenetics and molecular genetics have made it possible to identify an array of genomic abnormalities with prognostic and therapeutic significance. Hyperdiploidy > 50 chromosomes and ETV6-CBFA2 fusions have been used to identify low-risk cases, and BCR-ABL and MLL-AF4 to define high-risk leukemias. Despite their clinical utility, the risk classification system based on these findings lack absolute precision and should be complemented with other variables, the most important of which is the early blast cell response to remission induction therapy. Studies of tumor suppressor genes and proto-oncogenes in the BCL2 family genes may unravel the mechanisms of leukemia cell progression and the development of drug resistance, leading to innovative therapies. As the cure rates for childhood acute lymphoblastic leukemia (ALL) approach 80%, precise methods of risk assessment are needed to permit better selection of treatment that is neither excessive nor inadequate for individual patients. Because one or more genetic abnormalities underlie every case of leukemia, a risk assignment system based on primary genetic abnormalities has great intuitive appeal. Even though over 90% of childhood ALL cases can be readily classified according to numerical or gross structural chromosomal abnormalities, molecular analyses are essential to identify therapeutically relevant, submicroscopic genetic lesions not visible by karyotyping. This review focuses mainly on recent advances in genetic studies that have contributed to therapeutic advances or that hold promise for the future.
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PMID:Genetic abnormalities and drug resistance in acute lymphoblastic leukemia. 1050 Aug 13

We identified a novel human long fatty acyl CoA synthetase 2 gene, ACS2, as a new ETV6 fusion partner gene in a recurrent t(5;12)(q31;p13) translocation in a patient with refractory anemia with excess blasts (RAEB) with basophilia, a patient with acute myelogenous leukemia (AML) with eosinophilia, and a patient with acute eosinophilic leukemia (AEL). ACS2 is expressed in the brain and bone marrow and is highly conserved in man and rats. The resulting ETV6/ACS2 fusion transcripts showed an out-frame fusion of exon 1 of ETV6 to exon 1 of ACS2 in the AEL case, an out-frame fusion of exon 1 of ETV6 to exon 11 of ACS2 in the AML case, and a short in-frame fusion of ETV6 exon 1 to the 3' untranslated region of ACS2 in the RAEB case. Reciprocal ACS2/ETV6 transcripts were identified in two of the cases. Fluorescence in situ hybridization (FISH) analysis with ETV6 cosmids on 12p13, and BACs and P1s on 5q31, demonstrated that the 5q31 breakpoints of the AML and AEL cases involved the 5' portion of the ACS2 gene, and that the 5q31, breakpoint of the RAEB case involved the 3' portion of the ACS2 gene. None of the resulting chimeric transcripts except for the ACS2/ETV6 transcript in the RAEB case led to a fusion protein. Disruption of the second ETV6 allele by t(12;19) was detected in the AML case by FISH analysis. These observations suggest that the disruption of ETV6 and/or ACS2 may lead to the pathogenesis of hematologic malignancies with t(5;12)(q31;p13).
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PMID:Fusion of TEL/ETV6 to a novel ACS2 in myelodysplastic syndrome and acute myelogenous leukemia with t(5;12)(q31;p13). 1050 16

The improved outlook for children diagnosed today with acute lymphoblastic leukemia (ALL) over that 40 years ago is remarkable. With modern therapies and supportive care, complete remissions are achieved in up to 95% of patients and long-term disease-free survival rates approach 80%. Methotrexate is a key component in ALL consolidation and maintenance therapies and is administered intrathecally in the prophylaxis and treatment of central nervous system leukemia. Recent reports have significantly extended the results of preclinical studies of methotrexate response and resistance to patients with ALL. The application of new and sensitive molecular biology techniques makes it possible to study specific chromosomal and genetic alterations [t(12;21), hyperdiploidy, deletions or methylation of p15INK4B and p16INK4A] which potentially contribute to methotrexate response and resistance in childhood ALL. Studies of the relationships between genetic alterations and ALL progression, methotrexate pharmacology, and long term event-free-survivals may lead to the better identification of subgroups of patients who exhibit unique levels of sensitivity or resistance to chemotherapy including methotrexate. Further, by characterizing the roles of translocation-generated fusion genes (TEL-AML 1) and tumor suppressor genes (p15INK4B and p16INK4A) in treatment response, it may be possible to identify new and selective targets and/or treatment strategies for both children and adults with ALL who are refractory to current therapies.
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PMID:Molecular and cellular correlates of methotrexate response in childhood acute lymphoblastic leukemia. 1051 59

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

Because previous PCR-based methodologies for detection of minimal residual disease (MRD) in leukemia patients have been too cumbersome to allow for widespread clinical usefulness, we have employed a real-time quantitative PCR (RQ-PCR) system to develop an MRD assay for t(12;21). We initially determined the expression of the different alternatively spliced TEL-AML1 mRNAs found in t(12;21) breakpoint variants I and II. We then optimized PCR primers for the RQ-PCR system and, using the t(12;21)+ REH cell line in spiking experiments, found a linear detection of TEL-AML1 over at least five logs. Moreover, 1 malignant cell in a background of 1,000,000 normal cells could be detected. The expression of the GAPDH, ABL, and beta(2)-microglobulin (beta2M) housekeeping genes were then compared in normal donors and in leukemic patients, and the very stably expressed beta2M was selected as an internal reference gene, allowing us to compensate for variation in RNA quality and day-to-day variation. In 12 samples from t(12;21)-positive patients at diagnosis, the levels of the TEL-AML1 fusion transcripts were found to vary up to 14-fold after normalization to beta2M. Interestingly, in samples obtained from seven patients at diagnosis, during induction chemotherapy, or relapse, the level of TEL-AML1 in peripheral blood (PB) and bone marrow (BM) was found to differ only by threefold, suggesting that MRD may be evaluated in PB samples in most patients. We conclude that this assay could set new standards for t(12;21) MRD detection with its accuracy, its high throughput, and its short turnover time for samples. Genes Chromosomes Cancer 26:355-365, 1999.
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PMID:Rapid and sensitive minimal residual disease detection in acute leukemia by quantitative real-time RT-PCR exemplified by t(12;21) TEL-AML1 fusion transcript. 1053 71

The E-26 transforming specific (ETS)-related gene TEL, also known as ETV6, encodes a strong transcription repressor that is rearranged in several recurring chromosomal rearrangements associated with leukemia and congenital fibrosarcoma. The TEL protein contains two functional domains that have been partially characterized: a helix-loop-helix (HLH) domain (also known as a pointed domain) at the N-terminus, which physically interacts with itself, with the SUMO-conjugating enzyme UBC9, and with FLI1; and, at the C-terminus, an ETS domain with DNA-binding properties. Little is known about the function of the central region of TEL. The HLH domain and the central region of TEL are consistently maintained in the t(12;21), which is the most frequent chromosomal translocation involving TEL. In this study, we found that the HLH domain and the central region of TEL mediate transcription repression by two distinct mechanisms. The central region involves the recruitment of a repression complex, including SMRT and mSin3A. The HLH domain represses gene transcription through a mechanism that is independent of known corepressors. Thus, TEL belongs to a growing number of transcription factors rearranged by chromosomal translocations that are associated with the corepressor complexes.
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PMID:The leukemia-associated gene TEL encodes a transcription repressor which associates with SMRT and mSin3A. 1054 23

The Children's Cancer Group (CCG) found that children with moderate risk acute lymphoblastic leukemia (ALL) had an improved 5-year event-free survival (EFS) rate when treated with therapy that included a doubled delayed intensification (DDI) vs a single DI (SDI) phase. Because of increased toxicity with DDI, it is important to determine whether subgroups of children with ALL can be identified who have excellent outcomes with SDI therapy. TEL-AML1 fusion and hyperdiploid DNA content are present in the leukemic blasts of significant proportions of children with ALL and have been associated with an excellent prognosis. In this study, we retrospectively examined the impact of TEL-AML1 status and ploidy on treatment outcome in a cohort of 75 children with standard risk ALL treated at our institution between 1983 and 1993 with SDI therapy. TEL-AML1 fusion was present in 19/43 (44%) evaluable cases. Fifteen of 56 (27%) evaluable cases were classified as hyperdiploid based on a modal chromosome number of >/=51 and/or a DNA index of >/=1.16. The 7-year EFS was 81% for the 19 TEL-AML1-positive patients vs 54% for the 24 TEL-AML1-negative patients (P = 0.0264). In multivariate analyses, TEL-AML1-positive status was associated with a superior EFS (P = 0.02) even when the intial white blood count was included in the model. Overall survival (OS) at 7 years for TEL-AML1-positive patients was 100% vs 83% for TEL-AML1-negative patients (P = 0.0677). There were no differences in 7-year EFS or OS based on ploidy comparisons. These results underscore the need to examine closely the effects of treatment intensification on specific biologically defined subgroups of children with ALL.
Leukemia 1999 Nov
PMID:TEL-AML1 fusion identifies a subset of children with standard risk acute lymphoblastic leukemia who have an excellent prognosis when treated with therapy that includes a single delayed intensification. 1055 42

The TEL gene is involved in several chromosomal abnormalities of human hematopoietic malignancies. The chromosome 12 breakpoints frequently lie within the fifth intron of the gene, particularly in the most frequent translocation involving TEL, the t(12;21)(p13;q22). In order to search for a peculiar mechanism involved in the genesis of these translocations, we have established the sequence of two t(12;21) and a t(9;12)(q24;p13) breakpoints. Our data do not reveal the involvement of VDJ recombinase activity or Alu sequences but favor the occurrence of staggered breaks and DNA repair activity in the genesis of these translocations.
Leukemia 1999 Nov
PMID:Molecular analysis of chromosomal breakpoints in three examples of chromosomal translocation involving the TEL gene. 1055 49

We report on a series of Spanish patients with acute lymphoblastic leukaemia in whom the t(12;21) [TEL/AML1] translocation could not be identified with two sensitive techniques: reverse transcript-polymerase chain reaction (RT-PCR) and fluorescence in-situ hybridization (FISH). 101 cases were analysed: 38 children (29 B-cell precursor; nine T-cell precursor) and 63 adults (48 B-cell precursor; 15 T-cell precursor). Specific RT-PCR to amplify the TEL/AML1 fusion transcript was negative in all 101 cases. Moreover, all 38 paediatric samples were also negative by interphase FISH analysis for the presence of the TEL/AML1 fusion. These results suggest the existence of geographic/race variations in the genotype of acute lymphoblastic leukaemia (ALL).
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PMID:Low frequency of the TEL/AML1 fusion gene in acute lymphoblastic leukaemia in Spain. 1058 73

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


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