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Results for “ETS Translocation Variant 6 Protein”

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At least 19 recordsLinked to original sources
PubMed2003

Concurrent methylation of multiple genes in childhood ALL: Correlation with phenotype and molecular subgroup.

Multiple genes have been shown to be independently hypermethylated in lymphoid malignancies. We report here on the extent of concurrent methylation of E-cadherin, Dap-kinase, O(6)MGMT, p73, p16, p15 and p14 in 129 pediatric ALL cases. While most of these genes demonstrated methylation in a proportion of cases, O(6)MGMT, p16 and p14 were infrequently methylated (11, 7 and 3%, respectively). Methylation of at least one gene was found in the vast majority (83%) of cases. To determine the extent and concordance of methylation we calculated a methylation index (MI=number of methylated genes/number of studied genes) for each sample. The average MI was 0.28, corresponding to 2/7 methylated genes. MI was correlated with standard prognostic factors, including immunophenotype, age, sex, WBC and presence of specific translocations (TEL-AML1, BCR-ABL, E2A-PBX1 or MLL-AF4). We determined that children >/=10 years old and children presenting with high WBC (>/=50 x 10(9)/l) both associated with a higher MI (P<0.01 and <0.05, respectively). T-ALLs demonstrated a lower MI (median=0.17) than precursor B ALLs (median=0.28). Among the different molecular subgroups, MLL-ALLs had the highest MI (mean=0.35), while ALLs carrying the t(1;19) had the lowest MI (mean=0.07). The most common epigenetic lesion in childhood ALL was methylation of E-cadherin (72%) independent of the molecular subtype or other clinicopathological factors.

Adolescent↗
PubMed2003

Allelotype analysis in relapsed childhood acute lymphoblastic leukemia.

We performed for the first time the allelotype of relapsed childhood acute lymphoblastic leukemia (ALL). A total of 38 cases were screened for loss of heterozygosity (LOH) using 71 markers. In all, 26 (68%) patients showed LOH on at least one chromosomal arm, indicating that LOH is a frequent event at relapse. The most frequent loss was found on chromosomal arm 9p at the p16/INK4a locus (39%). LOH at the TEL gene locus on chromosomal arm 12p also occurred often (25%). Frequent loss was observed on chromosome arms 4q (20%), 6q (21%), and 17q (20%). Sequential analysis (i.e. samples obtained from both initial diagnosis and relapse) shows that some patients (63%) have the identical LOH status at both phases, suggesting the presence of the same clone. Other samples (37%) showed distinct LOH alterations, indicating clonal evolution at relapse. Despite the heterogeneous and complex changes, some shared LOH loci occurred in these matched samples, suggesting that many of the same tumor-suppressor genes are aberrant at both phases. In summary, novel tumor-suppressor genes on chromosome arms 4q, 6q, and 17q, as well as the p16 and TEL genes, have an important role in the relapse of childhood ALL.

Adolescent↗
PubMed2004

Modulation of Janus kinase 2 by cisplatin in cancer cells.

Constitutive activation of Janus kinases (JAKs) is frequently detected in various human cancers. The activation of JAKs results in the phosphorylation and activation of signal transducers and activators of transcription (STATs). The constitutive activation of JAK/STAT pathway may play an important role in growth and survival of human cancer cells. In this study, we examined whether a chemotherapeutic agent cisplatin could inhibit the JAK/STAT pathway. In ovarian cancer and sarcoma cells that express constitutively active JAK2, cisplatin significantly inhibited tyrosine phosphorylation and kinase activity of JAK2 in a dose- and time-dependent manner. Meanwhile, cisplatin also inhibited Stat3 tyrosine phosphorylation and down-regulated BcL-XL anti-apoptotic protein in the cancer cells tested. In leukemia cells expressing high level of TEL-JAK2 fusion protein, cisplatin dramatically inhibited tyrosine phosphorylation of TEL-JAK2 as well. Furthermore, our results have shown that down-regulation of JAK2 by cisplatin might be through modulation of a tyrosine phosphatase SHP-1 but not SOCS family members. Taken together, our observations demonstrated that cisplatin down-regulated the JAK/STAT pathway through de-phosphorylation of JAK/STAT in cancer cells.

Antineoplastic Agents↗
PubMed2004

Functional analysis of a dominant-negative DeltaETS TEL/ETV6 isoform.

A transcriptional repressor TEL belongs to the ETS family transcription factors and acts as a tumor suppressor. We identified five alternatively spliced TEL isoforms generated possibly through exon skipping mechanisms, by using reverse transcriptase-polymerase chain reaction analysis. Among them, we examined molecular and biological functions of a DeltaETS-TEL isoform (TEL-f). This isoform abrogated specific DNA-binding capacity to and trans-repressional ability through the ETS-binding site. Regardless, it showed dominant-negative effects over wild-type-TEL (TEL-a)-mediated transcriptional repression partly through sequestration of TEL-a from nucleus to cytoplasm. Moreover, TEL-f dominantly interfered with TEL-a-mediated erythroid differentiation in MEL cells and growth suppression in NIH3T3 cells. Interestingly, TEL isoforms without the entire (Delta exons 6+7-TEL) or a part (Delta exon 7-TEL) of ETS domain were expressed more frequently in myelodysplastic syndrome-derived leukemia than in myelodysplastic syndrome before transformation. This observation suggests that accumulation of the dominant-negative DeltaETS-TEL molecules could be a related phenomenon to leukemic progression of myelodysplastic syndrome.

Alternative Splicing↗
PubMed1997

Deletions of CDKN1B and ETV6 in acute myeloid leukemia and myelodysplastic syndromes without cytogenetic evidence of 12p abnormalities.

Seventy-nine acute myeloid leukemias (AML) and myelodysplastic syndromes without cytogenetic evidence of 12p aberrations were investigated by fluorescence in situ hybridization with probes for ETV6 and CDKN1B (previously called TEL and KIP1, respectively) to ascertain whether abnormalities of these genes are frequently undetected by standard chromosome banding analyses and, if so, whether they are associated with specific karyotypic patterns and morphologic features. One of sixty cytogenetically aberrant myeloid malignancies, an AML with a complex karyotype including del(5q) and del(20q), showed a hemizygous interstitial deletion of the ETV6 and CDKN1B loci. No concomitant rearrangement of the other ETV6 allele was detected. Two of nineteen cytogenetically normal AML displayed a hemizygous interstitial deletion involving CDKN1B, but not ETV6. Thus, cryptic deletions of these genes seem to be rare in cytogenetically abnormal myeloid malignancies without 12p aberrations (2%), whereas they may be more frequent in karyotypically normal AML (10%). Furthermore, the present findings show that the deletions may be narrow, not including the ETV6 gene, and indirectly suggest that CDKN1B, or a closely located genomic segment, is the target of 12p deletions.

Acute Disease↗
PubMed2006

Near-tetraploidy in childhood B-cell precursor acute lymphoblastic leukemia is a highly specific feature of ETV6/RUNX1-positive leukemic cases.

Near-tetraploidy (82-94 chromosomes) makes up fewer than 1% of childhood acute lymphoblastic leukemia (ALL) cases and has been reportedly associated with a possibly poorer prognosis compared with other ploidy groups. We analyzed 783 patients enrolled in the ALL-BFM-Austria 86, -90, -95, -99/2000 and Interfant-Austria 99 trials in order to assess its incidence, biological characteristics, and prognostic relevance. Twelve of 783 patients (1.5%) had a near-tetraploid ALL. Fluorescence in situ hybridization revealed that eight of the nine B-cell precursor (BCP) cases and none of the three T-cell ALL cases had an ETV6/RUNX1 rearrangement. After a median follow-up of 11.4 years, none of the patients has relapsed or died. Thus, near-tetraploidy appears to be a specific feature of ETV6/RUNX1+ BCP ALL cases that in turn may explain its excellent outcome.

Adolescent↗
PubMed1999

A physical, transcript, and deletion map of chromosome region 12p12.3 flanked by ETV6 and CDKN1B: hypermethylation of the LRP6 CpG island in two leukemia patients with hemizygous del(12p).

FISH analyses and loss of heterozygosity studies have delineated a commonly deleted region in hematological malignancies flanked by ETV6 and CDKN1B on chromosome 12p12.3. The same chromosomal region is also a target for deletions in certain solid tumors. As an initial step toward the cloning of a potential tumor suppressor gene at 12p12.3, we mapped the ETV6-CDKN1B region physically using bacterial artificial chromosome (BAC) and P1-derived clone (PAC) contigs. The 1.2-Mb high-resolution, contiguous map extends from D12S1095 to D12S929 and consists of 19 PACs and 20 BACs. Pulsed-field gel electrophoresis experiments confirmed the integrity of the clone-based map and identified six CpG islands in the region. A transcript map was generated by performing hybridization selection experiments with the genomic clones, by evaluating known 12p ESTs for their presence in the contig, and by sequence analysis of CpG islands in the region. Altogether evidence was gathered for the presence of the recently published LRP6 gene and at least seven other new genes in this chromosomal region. The CLAPS3 gene, mapped between D12S391 and D12S358, was reassigned to chromosome 5 since genomic sequencing demonstrated the chromosome 12p sequence to be a pseudogene. Polymorphic CA repeats were identified approximately every 100 kb, which will support future analysis of loss of heterozygosity in tumors. Fluorescence in situ hybridization analysis of leukemia patients with del(12p) further refined the commonly deleted segment to 600 kb between ETV6 and D12S358, which apparently excludes CDKN1B. Methylation changes of the CpG islands in the ETV6-CDKN1B interval were assessed by Southern analysis for leukemia patients with hemizygous 12p deletions. A "de novo" methylation was detected only at the LRP6 CpG island in 2 of 22 leukemia patients tested and was confirmed by methylation-sensitive PCR and sequencing. The genomic structure of LRP6 was elucidated to allow screening for inactivating mutations, but only intragenic polymorphisms were identified. Hypermethylation of CpG islands associated with gene promoters is reported as a common mechanism for gene silencing and tumor suppressor inactivation. Therefore the consequences of the LRP6 CpG island methylation and its role in the observed phenotype need further investigation.

Cell Cycle Proteins↗
PubMed2005

The presence of TEL/AML1 rearrangement and cryptic deletion of the TEL gene in adult acute lymphoblastic leukemia (ALL).

TEL/AML1 (also known as ETV6/RUNX1) rearrangement is the most frequent genetic change in childhood B-acute lymphoblastic leukemia (ALL) and is associated with a favorable prognosis. Its presence in adult ALL, however, has been questionable, and any association between TEL/AML1 rearrangement and clinical prognosis is unknown. To reveal the presence and incidence of the TEL/AML1 rearrangement in adult ALL, we applied fluorescence in situ hybridization (FISH). We conducted extra-signal, dual-color fluorescence in situ hybridization (ES-FISH) for TEL/AML1 rearrangement on bone marrow cells from 74 adult ALL patients and analyzed the survival time. We demonstrated the TEL/AML1 rearrangement in 2 patients (2.7%) among 74 patients with ALL. Of 74 adult ALL patients, 3 (4.0%) showed deletion of the TEL gene without TEL/AML1 rearrangement. The mean survival time of patients with TEL/AML1+ALL and patients with cryptic TEL deletion was 33 and 5 months, respectively, whereas the mean survival time of 53 TEL/AML1-ALL patients was 16.7 months. TEL/AML1 rearrangement is not unique in childhood ALL, and cryptic TEL deletion without TEL/AML1 rearrangement was more frequent than the TEL/AML1 rearrangement in adult ALL. We recommend TEL/AML1 FISH in adult ALL patients because conventional cytogenetic studies so far have yielded uninformative results.

Adult↗
PubMed2006

Identification of the nuclear localization motif in the ETV6 (TEL) protein.

ETV6, or Translocation-Ets-Leukemia (TEL), is an ETS family transcriptional repressor that is essential for establishing hematopoiesis in neonatal bone marrow, and is frequently a target of chromosomal translocations in human cancer. ETV6 is predominantly a nuclear phosphoprotein that represses transcription by binding directly to the promoters of target genes. The nuclear localization mechanism of ETV6, however, is not well understood. In this report, we provide evidence that a nuclear localization signal (NLS) exists in the C-terminal region of ETV6. ETV6 proteins with mutations outside of amino acids 332-452 localize to the nucleus, whereas proteins with mutations within amino acids 332-452 remain in the cytoplasm. Furthermore, when a fragment of ETV6 comprised of amino acids 332-452 was fused to cytoplasmic beta-galactosidase protein, the fusion protein was able to enter the nucleus. These results strongly indicate that residues 332-452 mediate nuclear localization of ETV6.

Amino Acid Motifs↗
PubMed1999

Fine physical and transcript mapping of a 1.8 Mb region spanning the locus for childhood acute lymphoblastic leukemia on chromosome 12p12. 3.

Rearrangements of the short arm of chromosome 12 are frequently observed in hematological disorders. Previous studies of loss of heterozygosity identified a small genetic interval on chromosome 12p12.3 that is frequently deleted in childhood acute lymphoblastic leukemia (ALL). Two genes, ETV6/TEL and p27/KIP1, are located in this interval. Evidence has accumulated that an as-yet unidentified tumor suppressor gene is closely linked to these. To facilitate the identification of candidate genes, a long-range high-resolution restriction map of the ALL locus was constructed using a contig of YAC clones. Several marker loci, including 11 STS, three newly developed YAC end-based STS, six EST, and seven genes were unambiguously positioned in the new map. The map covers 1.8Mb and extends from the distal salivary proline-rich protein gene cluster to the proximal p27/KIP1 gene. The data confirmed the order tel-D12S358-p27/KIP1-cen and excluded p27/KIP1 as a candidate tumor suppressor gene. The critical region delimited by D12S89 and D12S358 is a 750kb CpG-island rich region that includes the 240kb TEL/ETV6 gene as well as CLAPS3 (clathrin-adaptor small chain 3). The new map provides a molecular framework for the identification of novel genes and transcriptional units in the ALL interval.

Adaptor Protein Complex 3↗
PubMed2000

Insights into the biologic and molecular abnormalities in adult acute lymphocytic leukemia.

The last 3 decades have seen much progress in the treatment and outcome of patients with ALL. Unfortunately, the success that has been achieved in children with ALL has not yet been translated into adult patients. Insight into the biologic and molecular abnormalities in ALL may, however, provide the necessary clues that allow a clearer understanding of the crucial differences in the behavior of ALL in different groups of patients. As the molecular basis of the disease is deciphered, new targets are discovered that may prove useful for therapeutic interventions in the future.

Adult↗
PubMed1997

Ovarian cancer has frequent loss of heterozygosity at chromosome 12p12.3-13.1 (region of TEL and Kip1 loci) and chromosome 12q23-ter: evidence for two new tumour-suppressor genes.

Identification of the key genetic alterations leading to ovarian cancer is in its infancy. Polymerase chain reaction (PCR)-based analysis of loss of heterozygosity (LOH) is a powerful method for detecting regions of altered tumour-suppressor genes. Focusing on chromosome 12, we examined 23 ovarian cancer samples for LOH using 31 highly polymorphic microsatellite markers and found the chromosomal localization of two putative tumour-suppressor genes. Two commonly deleted regions were 12p12.3-13.1 in 6/23 (26%) and 12q23-ter in 7/23 (30%) samples. LOH on chromosome 12 was more common in late-stage ovarian carcinomas. The region of LOH at 12p12.3-13.1 includes the genes that code for the ETS-family transcriptional factor, known as TEL, and the cyclin-dependent kinase inhibitor, known as p27Kip1. Mutational analysis of both TEL and p27Kip1 using single-strand conformation polymorphism (SSCP) showed no abnormalities, suggesting that the altered gene in this region is neither of these genes. Taken together, our data suggest that new tumour-suppressor genes in the region of chromosomes 12p12.3-13.1 and 12q23-ter may be involved in the development of ovarian cancer.

Adenocarcinoma↗
PubMed1997

Lack of ETV6 (TEL) gene rearrangements or p16INK4A/p15INK4B homozygous gene deletions in infant acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) occurring in infants less than 1 year of age differs clinically and biologically from that observed in older children. Cytogenetically, 11q23 translocations are detected in approximately 50% of infant ALLs and fuse the 11q23 gene HRX with a variety of partner chromosomal loci. Overall, HRX rearrangements are detected molecularly in 70-80% of infant ALLs as compared to 5-7% of ALLs arising in older children. Two recently described molecular abnormalities in childhood ALL are ETV6 gene rearrangements and homozygous deletions of p16(INK4A) and/or p15(INK4B). Each of these abnormalities occurs in 15-20% of all childhood ALLs, and neither can be accurately identified by routine cytogenetic analyses. The incidence of these genetic abnormalities and their potential relationship to HRX gene status in infant ALL is unknown. Using Southern blot analyses, we determined ETV6 and p16(INK4A)/p15(INK4B) gene status in a cohort of infant ALLs. No ETV6 rearrangements or homozygous deletions (n=69) or homozygous p16(INK4A) and/or p15(INK4B) gene deletions (n=54) were detected in any of the infant ALLs. Therefore, ETV6 and p16(INK4A)/p15(INK4B) do not play a significant role in the pathogenesis of infant ALL, further emphasizing the distinctive biology of this subset of leukemias.

Carrier Proteins↗
PubMed2004

Split-signal FISH for detection of chromosome aberrations in acute lymphoblastic leukemia.

Chromosome aberrations are frequently observed in precursor-B-acute lymphoblastic leukemias (ALL) and T-cell acute lymphoblastic leukemias (T-ALL). These translocations can form leukemia-specific chimeric fusion proteins or they can deregulate expression of an (onco)gene, resulting in aberrant expression or overexpression. Detection of chromosome aberrations is an important tool for risk classification. We developed rapid and sensitive split-signal fluorescent in situ hybridization (FISH) assays for six of the most frequent chromosome aberrations in precursor-B-ALL and T-ALL. The split-signal FISH approach uses two differentially labeled probes, located in one gene at opposite sites of the breakpoint region. Probe sets were developed for the genes TCF3 (E2A) at 19p13, MLL at 11q23, ETV6 at 12p13, BCR at 22q11, SIL-TAL1 at 1q32 and TLX3 (HOX11L2) at 5q35. In normal karyotypes, two colocalized green/red signals are visible, but a translocation results in a split of one of the colocalized signals. Split-signal FISH has three main advantages over the classical fusion-signal FISH approach, which uses two labeled probes located in two genes. First, the detection of a chromosome aberration is independent of the involved partner gene. Second, split-signal FISH allows the identification of the partner gene or chromosome region if metaphase spreads are present, and finally it reduces false-positivity.

Basic Helix-Loop-Helix Proteins↗