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

About 25% of the children with pre-B cell acute lymphoblastic leukemia (ALL) have a chromosomal translocation of t(1;19)(q23;p13). This translocation juxtaposes the E2A gene on chromosome 19 to the PBX1 gene on chromosome 1, leading to production of a fusion transcript. The fusion sites of the E2A and PBX1 coding sequence have been identical among all cases of t(1;19) ALL studied so far. Here we described a new fusion site of the E2A and PBX1 genes, which was detected in the leukemic blasts of a child with t(1;19) pre-B ALL using the reverse transcriptase polymerase chain reaction and direct sequencing. The fusion site was located just upstream of the DNA binding domain of the E2A gene, and was close to a homeodomain of the PBX1 gene.
Leukemia 1993 Sep
PMID:New E2A/PBX1 fusion transcript in a patient with t(1;19)(q23;p13) acute lymphoblastic leukemia. 810 13

The t(1;19)(q23;p13), a non-random chromosome rearrangement associated with childhood pre-B acute lymphoblastic leukemia (ALL), results at molecular level in the hybrid E2A-PBX1 gene. This gene is expressed in a typical set of fusion transcripts and oncogenic chimeric proteins. However, the occurrence of t(1;19) molecular variants has been recently suggested. In an attempt to identify these variants, we analyzed 25 pediatric cases of pre-B cIg+ cell ALL. We used Southern blot analysis to detect E2A gene rearrangements and RT-PCR to detect chimeric E2A-pbx1 transcripts. In addition to seven cases with the molecular pattern usually associated with the t(1;19), we identified three molecular variants. In one case, a variant E2A-pbx1 transcript showed 27 additional base pairs inserted in frame at the junction site. In two cases, Southern blot evidenced the expected E2A gene rearrangements. However, extensive RT-PCR analysis failed to detect any E2A-pbx1 transcript. These findings led us to hypothesize that a gene other than PBX1 might be involved in these 1;19 variant translocations.
Leukemia 1994 Apr
PMID:Molecular variants of the 1;19 chromosomal translocation in pediatric acute lymphoblastic leukemia (ALL). 815 50

The translocation t(1;19)(q23;p13) in pediatric patients with acute lymphoblastic leukemia (ALL) was demonstrated in early reports to result in a consistent fusion between the E2A and PBX1 gene sequences and in the expression of a uniform, chimeric E2A/PBX1 mRNA with transforming potential. More recent observations suggested that cytogenetically identical t(1;19) translocations can result in the transcription of different mRNA species and that expression of the E2A/PBX1 message may be restricted to patients with the t(1;19) who display a pre-B phenotype of ALL. To further assess the correlation between the immunologic subtypes of the disease and specific genetic alterations, we have performed cytogenetic and molecular analyses in 221 children with B-lineage ALL. Expression of the chimeric E2A/PBX1 message was detected in 21 patients. Out of 14 patients, in whom cytoplasmic immunoglobulin (cig) analyses were available, no less than four had a cig- B-cell precursor ALL, whereas 10 displayed a cig+ B-ALL immunophenotype. These findings are at variance with a recent report in which expression of the E2A/PBX1 message was linked exclusively to a subset of patients who displayed a cig+ pre-B-cell precursor phenotype of ALL. In seven cases diagnosed before 1986, cig analyses were not available, and consequently E2A/PBX1 expression could not be correlated to a particular immunological subtype of B-cell precursor ALL. Our results have important implications for the detection of residual disease in pediatric patients where expression of the typical E2A/PBX1 mRNA may occur both in cig+ (pre-B) and cig- (early pre-B) immunologic subtypes of ALL.
Leukemia 1993 Dec
PMID:Expression of identical E2A/PBX1 fusion transcripts occurs in both pre-B and early pre-B immunological subtypes of childhood acute lymphoblastic leukemia. 825 5

The very rapid development in the last few years of techniques based on use of the polymerase chain reaction (PCR) for characterizing molecular lesions in leukaemia and lymphoma now offers the opportunity for monitoring residual disease at a sensitivity of one malignant cell in 10(5) or 10(6) normal cells. Maximal specificity is presumably achieved when the DNA sequences amplified are truly leukaemia-specific, such as BCR/ABL in chronic myelogenous leukemia, RARA PML/RARA in t(15;17) acute myelogenous leukemia, DEK/CAN in t(6;9) AML, PBX1/E2A in t(1;19) acute lymphoblastic leukemia (ALL), or TAL-1 deletions in other T-ALLs. Comparable sensitivity may be achieved by using immunoglobulin heavy chain (IGH) and T-cell receptor (TCR) gene rearrangements if a clonospecific probe can be generated. However, the presence of similar sequences in IgH genes from normal B lymphocytes may decrease the specificity. For clinical purposes the crucial issues are the following. Can PCR techniques be used for confirmation of diagnosis and evaluation of extent of disease? Can PCR data obtained in remission provide information about the probability of cure or of relapse? Can techniques be developed to quantitate the PCR product and thereby increase its predictive value? These and other issues were addressed at the 4th Workshop of the Molecular Biology/BMT Study Group that took place in Bristol UK on 9-10 May 1992.
Leukemia 1993 Aug
PMID:Molecular evidence of minimal residual disease after treatment for leukaemia and lymphoma: an updated meeting report and review. 835 Jun 33

The E2A/PBX1 and the BCR/ABL fusion genes result from the t(1;19)(q23;p13) and the t(9;22)(q34;q11), respectively, and encode oncoproteins which are thought to play an important role in the development of acute lymphoblastic leukemia (ALL) subtypes associated with adverse prognosis. The use of the polymerase chain reaction (PCR) for the detection of these genetic rearrangements may offer advantages over cytogenetic techniques which are often unsatisfactory in patients with ALL and, furthermore, provide a useful tool for monitoring of residual disease. However, it has not yet been evaluated whether the employment of PCR at the time of diagnosis improves the detection rate of these clinically relevant genetic anomalies. We have developed a multiprimer-PCR protocol which facilitates the detection of each of the four chimeric E2A/PBX1 and BCR/ABL mRNAs in a single reaction. This protocol was used for the evaluation of bone-marrow or blood samples from 251 children with ALL in whom cytogenetic analyses had been performed. Of the 251 patients, 221 had a B-cell precursor immunophenotype. In this group, 21 patients (9.5%) carrying the E2A/PBX1 rearrangement and three patients (1.4%) with BCR/ABL transcripts were detected by PCR. Twelve of these cases had escaped the detection by conventional cytogenetic analysis. In two of 12 patients with a typical t(1;19)(q23;p13), no E2A/PBX1 transcripts were identified by PCR, thus suggesting the presence of different molecular rearrangements. Residual leukemic cells were detected by PCR in five of eight patients who were followed during complete clinical remission. The frontline use of PCR has an important impact on the timely diagnosis, therapeutic decisions, and monitoring of high-risk patients with B-cell precursor leukemia who carry the E2A/PBX1 or BCR/ABL fusion genes.
Leukemia 1993 May
PMID:Detection and clinical relevance of genetic abnormalities in pediatric acute lymphoblastic leukemia: a comparison between cytogenetic and polymerase chain reaction analyses. 848 19

This manuscript describes a protocol for the utilization of glass slide preparations of hematologic specimens for the recovery of mRNA that is of a quality suitable for the reverse transcription-polymerase chain reaction (RT-PCR) detection of specific gene expression. Total cellular RNA obtained from archival bone marrow aspirate smears of 23 leukemia patients, which had been stored for periods of time from 1 day to 34 mo, were extracted, and 1 to 2 micrograms of each were subjected to RT-PCR using primer pairs specific for the amplification of beta-actin cDNA. Three pairs of primers for the amplification of beta-actin cDNAs of 83,260, and 540 base pairs were used to evaluate the length of mRNA that could be analyzed; the results indicate the consistent amplification of cDNA for the short- and intermediate-sized fragments as revealed by ethidium bromide fluorescence of agarose gel-resolved PCR products. To address the utility of RT-PCR analysis towards the detection of mRNA associated with specific gene alterations in such specimens, a primer pair for amplification of the E2A-PBX1 fusion cDNA was used in PCRs of RT cDNAs for each of the 23 specimens, three of which were pre-B-cell acute lymphoblastic leukemias known to have the t(1;19) karyotype alteration resulting in the fusion of the E2A and PBX1 genes. Agarose gel electrophoresis analysis of the products of these RT-PCR amplifications revealed the amplification of the fusion gene cDNA in only those cases for which there was cytogenetic documentation of t(1;19); these results were confirmed by the Southern filter hybridization of an internal E2A-PBX1 oligonucleotide.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:RT-PCR detection of mRNA recovered from archival glass slide smears. 848 91

The t(1;19) is the most frequent recurring chromosomal translocation in childhood acute lymphoblastic leukaemia (ALL). In most cases typical chimaeric E21-PBX1 transcripts are expressed as a consequence of this rearrangement, allowing the molecular detection of the t(1;19) at the RNA level. This translocations has been associated with a poor clinical outcome, although intensified chemotherapy has been reported to nullify its adverse prognostic impact. We therefore used reverse transcriptase/polymerase chain reaction (RT-PCR) to detect residual leukaemic cells at successive times during treatment and to monitor the response to chemotherapy in six t(1;19)-positive ALL pediatric patients. Five of these patients rapidly achieved molecular remission and no evidence of minimal residual disease (MRD) was found in the remission bone marrows beyond the third month of treatment. One patient still displayed residual leukaemic cells at the end of therapy, although she has been in continuous complete clinical remission (CCR) for 84 months. However, this patient is peculiar in our series in that two different types of chimaeric E2A-PBX1 transcripts were expressed in her leukaemic cells, only one being detectable in remission.
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PMID:Reverse transcriptase/polymerase chain reaction follow-up and minimal residual disease detection in t(1;19)-positive acute lymphoblastic leukaemia. 861 31

Mice transgenic for the leukemia oncogene E2A-PBX1 invariably develop lethal, high-grade T-cell lymphomas by 5 months of age. In this study, retroviral insertional mutagenesis was employed to identify oncogenes that cooperate with the E2A-PBX1 transgene in lymphomagenesis. Neonatal retroviral infection substantially reduced length of survival due to accelerated development of lymphomas (81 versus 130 days). The Pim1 gene was targeted by retroviral insertions in 48% of accelerated lymphomas whereas less than 5% contained activated c-Myc and none contained activated Pim2. However, Pim1 DNA rearrangements were frequently sub-stoichiometric and not present at all sites of involvement in an otherwise monoclonal lymphoma indicating that Pim1 activation occurred late in the course of lymphomagenesis. Tumor subpopulations containing activated Pim1 alleles displayed a substantial growth advantage over Pim1 negative cells following serial transfer to secondary, syngeneic recipients. Cooperative interactions were observed in intercrossed Pim1 and E2A-PBX1 transgenic mice in which all double transgenic progeny developed lethal, diffuse T lineage lymphomas by 3 months of age, whereas only 13% of E2A-PBX1 and none of Pim1 single transgenic intercross progeny developed lymphomas by 1 year. Tumors from double transgenic mice were monoclonal providing evidence that additional genetic events were required for transformation. Therefore, Pim1 and E2a-Pbx1 cooperate in T lineage lymphomagenesis but they are not sufficient and the role of Pim1 is more likely to be associated with tumor progression.
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PMID:Pim1 cooperates with E2a-Pbx1 to facilitate the progression of thymic lymphomas in transgenic mice. 940 Oct

The p16INK4A (p16) and p15INK4B (p15) tumor suppressor genes are inactivated by homozygous gene deletion and p15 promoter hypermethylation in a significant proportion of childhood acute lymphoblastic leukemias (ALLs). However, little is known about the potential association between p16/p15 gene alterations and specific genetic abnormalities implicated in leukemogenesis. The t(1;19)(q23;p13) and t(17;19)(q21-22;p13) are non-random translocations observed in childhood ALL that create distinct E2A fusion proteins: E2A-PBX1 and E2A-HLF, respectively. Previously, a negative association was found between the t(1;19) and homozygous p16/p15 deletions. In this study we determined p16 and p15 gene status in additional t(1;19)+ ALLs and compared this incidence to that observed in t(17;19)+ ALLs. No homozygous p16 or p15 deletions were observed among 13 t(1;19)+ ALLs analyzed. In contrast, homozygous deletions of both p16 and p15 were present in two of four t(17;19)+ ALLs. None of 10 t(1;19)+ ALLs contained p15 promoter hypermethylation. In contrast, one of the two t(17;19)+ ALLs that lacked p15/p16 homozygous deletions showed probable hemizygous p15 hypermethylation. We conclude that homozygous p16 and/or p15 deletions and p15 hypermethylation rarely accompany E2A-PBX1 fusion, but occur in concert with E2A-HLF fusion in a subset of t(17;19)+ ALLs. These findings suggest that there may be different modes of cooperative leukemogenesis in ALLs associated with different E2A fusion proteins.
Leukemia 1998 Sep
PMID:Different patterns of homozygous p16INK4A and p15INK4B deletions in childhood acute lymphoblastic leukemias containing distinct E2A translocations. 973 91

The proto-oncogene Fli-1, a member of Ets family is rearranged or activated through proviral integration in erythroleukemias, induced by Friends' Murine Leukemia Virus. The DNA binding domain (ETS domain) of Fli-1 is fused to the RNA binding domain of EWS by t(11q24:22q12) chromosomal translocation in Ewing's sarcoma and primitive neuroectodermal tumors. Screening of human cDNA libraries has identified two different 5'-termini and alternatively spliced forms of the human Fli-1 gene (Fli-1b), suggesting the possible existence of two independent promoters. The genomic sequence adjacent to the alternate exon of human Fli-1b gene shows functional promoter activity when cloned in promoter-less CAT expression vector and transfected into QT-6 cells. The transcription initiation (CAP) site and minimum promoter region necessary for function were localized. The 5'-flanking regions of human Fli-1b and mouse Fli-1 show 80% homology suggesting conserved promoter regulatory elements. The Fli-1b 5'-flanking sequence lacks canonical TATA or CCAAT boxes but contains a partially conserved TATA-like sequence at position 242. Several transcription factor binding sequences like ATF/CREB, E2A-PBX1, EBP, PEA-3, ETS-2, Sp-1, c-Myc, TBP, GATA-1 and Oct-3 were conserved in the promoter sequence. Functional promoter assays revealed that Fli-1b promoter shows very strong transcriptional activation compared to Fli-1 promoter. We also showed that variant Fli-1b has transcriptional activation properties similar to those of Fli-1. Fli-1b and Fli-1 show differential expression in various hematopoietic cell lines. This differential expression and promoter activities of Fli-1 and Fli-1b suggests that several mechanisms are involved in Fli-1 gene regulation which are mediated by many transcription factors.
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PMID:Fli-1b is generated by usage of differential splicing and alternative promoter. 976 25


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