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Results for “ETS Translocation Variant 6 Protein”

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At least 217 records · Page 12Linked to original sources
PubMed2006

RNAi-mediated silencing of TEL/AML1 reveals a heat-shock protein- and survivin-dependent mechanism for survival.

The TEL/AML1 fusion gene results from the most frequent t(12;21)(p13;q22) translocation in childhood acute lymphoblastic leukemia (ALL). Its contribution to transformation is largely unknown, in particular with respect to survival and apoptosis. We therefore silenced TEL/AML1 expression in leukemic REH cells by RNA inhibition, which eventually led to programmed cell death. Microarray and 2D gel electrophoresis data demonstrated a differential regulation of heat-shock proteins (HSPs), among them HSP90, as well as of its client, survivin. Consistent with these findings, ectopic expression of TEL/AML1 in Ba/F3 cells increased protein levels of HSP90 and survivin and conferred resistance to apoptotic stimuli. Our data suggest that TEL/AML1 not only contributes to leukemogenesis by affecting an antiapoptotic network but also seems to be indispensable for maintaining the malignant phenotype. The functional relationship between TEL/AML1, HSP90, and survivin provides the rational for targeted therapy, be it the fusion gene or the latter 2 proteins.

Base Sequence↗
PubMed2004

Near-triploid acute lymphoblastic leukemia with TEL/AML1 translocation.

An 11-year-old girl was diagnosed as B-precursor acute lymphoblastic leukemia (ALL) with co-expression of myeloid antigens. Cytogenetic analysis revealed a near-triploid (75-82 chromosomes/cell) abnormal chromosomal complement. Fluroscent in situ hybridization studies indicated presence of TEL/AMLI fusion genes. We discuss the prognostic relevance of TEL/AML1 in this rare near-triploid subtype of ALL.

Burkitt Lymphoma↗
PubMed2005

Up-regulation of glutathione biosynthesis in NIH3T3 cells transformed with the ETV6-NTRK3 gene fusion.

The ETV6-NTRK3 gene fusion, first identified in the chromosomal translocation in congenital fibrosarcoma, encodes a chimeric protein tyrosine kinase with potent transforming activity. ETV6-NTRK3-dependent transformation involves the joint action of NTRK3 signaling pathways, and aberrant cell cycle progression resulting from activation of Mek1 and Akt. The level of glutathione (GSH) was found to be markedly increased in ETV6-NTRK3-transformed NIH3T3 cells. The activities of the two GSH biosynthetic enzymes as well as of glutathione peroxidase, together with their mRNAs, were also higher in the transformed cells. The transformed cells were able to grow in the presence of GSH-depleting agents, whereas the control cells were not. L-Buthionine-(S,R)-sulfoximine (BSO) inhibited activation of Mek1 and Akt in the transformed NIH3T3 cells. These observations imply that up-regulation of GSH biosynthesis plays a central role in ETV6-NTRK3-induced transformation.

Animals↗
PubMed1996

High incidence of TEL/AML1 fusion resulting from a cryptic t(12;21) in childhood B-lineage acute lymphoblastic leukemia in Taiwan.

Despite its rarity by routine karyotypic analysis, cryptic t(12;21)(p12-13;q22) translocation leading to TEL/AML1 fusion has been recognized as the most frequent genetic rearrangement in childhood acute lymphoblastic leukemia (ALL) in two recent studies, one from France and the other from the United States. To estimate the frequency of this abnormality in the Chinese population, we studied 41 children with ALL and 17 with acute myeloid leukemia (AML) in two medical centers in Taiwan, using the reverse transcriptase polymerase chain reaction (RT-PCR) assay. Results of this analysis demonstrated a 17% frequency of this translocation in the ALL population overall and 19% in patients with B-lineage ALL, similar to previous findings in Caucasian children. None of the patients with AML had TEL/AML1 fusion transcripts. In addition to its association with the B-lineage immunophenotype, TEL/AML1 was also correlated with a low presenting leukocyte count and favorable age (1-10 years). These findings, combined with earlier reports, indicate that TEL/AML1 fusion is the most frequent genetic abnormality in childhood ALL, regardless of race. Molecular diagnosis of t(12;21)-positive ALL may identify a subgroup of patients who do not require intensive treatment for cure.

Adolescent↗
PubMed2006

FLT3 is fused to ETV6 in a myeloproliferative disorder with hypereosinophilia and a t(12;13)(p13;q12) translocation.

The FMS-like tyrosine kinase 3 (FLT3) gene, belonging to the receptor tyrosine kinase (TK) subclass III family, plays an important role in normal hematopoiesis and is one of the most frequently mutated genes in hematologic malignancies as well as an attractive target for directed inhibition. Activating mutations of this gene, including internal tandem duplication in the juxtamembrane (JM) domain and point mutations in the TK domain, are found in approximately one-third of patients with acute myeloid leukemia and in a smaller subset of patients with acute lymphoblastic leukemia. We report here that FLT3 may contribute to leukemogenesis in a patient with myeloproliferative disorder and a t(12;13)(p13;q12) translocation through generating a fusion gene with the ETS variant gene 6 (ETV6) gene. ETV6 has been reported to fuse to various partner genes, including TK and transcription factors. Both ETV6/FLT3 and reciprocal FLT3/ETV6 transcripts were detected in the patient mRNA by reverse transcriptase-polymerase chain reaction. At the protein level, however, only ETV6/FLT3 products were expressed. Among them, one retains the helix-loop-helix (HLH) oligomerization domain of ETV6 and the JM as well as TK domain of FLT3. FLT3 receptor in leukemic cells might be inappropriately activated through dimerization by HLH domain of ETV6, which consequently interfered with proliferation and differentiation of hematopoietic cells.

Aged↗
PubMed2002

The utility of spectral karyotyping in the cytogenetic analysis of newly diagnosed pediatric acute lymphoblastic leukemia.

We applied multicolor spectral karyotyping (SKY) to a panel of 29 newly diagnosed pediatric pre B-cell ALLs with normal and abnormal G-banded karyotypes to identify cryptic translocations and define complex chromosomal rearrangements. By this method, it was possible to define all add chromosomes in six cases, a cryptic t(12;21)(p13;q11) translocation in six cases, marker chromosomes in two cases and refine the misidentified aberrations by G-banding in two cases. In addition, we identified five novel non-recurrent translocations - t(2;9)(p11.2;p13), t(2;22) (p11.2;q11.2), t(6;8)(p12;p11), t(12;14)(p13;q32) and t(X;8)(p22.3;q?). Of these translocations, t(2;9), t(2;22) and t(12;14) were identified by G-banding analysis and confirmed by SKY. We characterized a t(12;14)( p13;q32) translocation by FISH, and identified a fusion of TEL with IGH for the first time in ALL. We identified a rearrangement of PAX5 locus in a case with t(2;9)(p11.2;p13) by FISH and defined the breakpoint telomeric to PAX5 in der(9)t(3;9)(?;p13). These studies demonstrate the utility of using SKY in combination with G-banding and FISH to augment the precision with which chromosomal aberrations may be identified in tumor cells.

Acute Disease↗
PubMed2002

Mutational analysis of ETV6 in prostate carcinoma.

BACKGROUND: In an effort to better understand the molecular events responsible for progression of prostate carcinoma to metastatic disease, we have recently identified a homozygous deletion at 12p12-13 involving ETV6 (tel). Although mutational analysis of ETV6 has not been examined previously in prostate carcinoma, it is an attractive candidate prostate cancer tumor suppressor gene since as it previously has been implicated in malignancy. Therefore, we decided to analyze 43 prostate cell lines, xenografts, and metastatic foci for inactivating mutations. METHODS: DNA was isolated from 7 cell lines, 18 xenografts, and 18 metastatic deposits. Single-strand conformational polymorphism (SSCP) analysis of ETV6, was performed by polymerase chain reaction (PCR) amplification of each exon by using intron specific primers. PCR products were then resolved by gel electrophoresis, and aberrantly migrating PCR products were then sequenced. RESULTS: Two previously described polymorphisms and four novel sequence changes were identified. Polymorphisms at nucleotide 258 (G --> A, Thr --> Thr) and 602 (T --> C, Leu --> Pro) were identified in eight and one specimen(s), respectively. Analysis of noncancerous DNA confirmed the presence of the polymorphisms in the germ-line. Four possible mutations were identified at nucleotides 24 (T --> G, Cys --> Trp), 380 (G --> A, Arg --> Glu), 776 (G --> T, Arg --> Leu), and 876 (C --> T, Leu --> Leu). Three were in xenografts or cell lines. Because normal DNA was not available, these could represent rare polymorphisms. The sole mutation in a clinical specimen, at nucleotide 876, did not result in an amino acid change. CONCLUSION: Our data suggest that mutational inactivation ETV6 may occur in prostate carcinoma. The functional significance of these potential inactivating mutations remains to be determined.

Carcinoma↗
PubMed1999

Genetic abnormalities and drug resistance in acute lymphoblastic leukemia.

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.

Burkitt Lymphoma↗
PubMed2001

Mechanisms of transcriptional repression by the t(8;21)-, t(12;21)-, and inv(16)-encoded fusion proteins.

AML-1 is one of the most frequently translocated genes in human leukemia. AML-1 binds DNA and activates or represses transcription, while the chromosomal translocation fusion proteins in acute myeloid leukemia subvert these functions. The t(8;21) is the second most frequent translocation in acute myeloid leukemia and creates a fusion between the DNA binding domain of AML-1 and the ETO (also known as MTG8) corepressor. The t(12;21) is found in up to 25% of pediatric B cell acute lymphoblastic leukemias and fuses the ETS family transcription factor TEL to the amino terminus of AML-1. In addition, the inv(16), the most frequent translocation in acute myeloid leukemia, fuses the AML-1 cofactor CBFbeta to the smooth muscle myosin heavy chain MYH11. Both the t(8;21) and t(12;21) create transcriptional repressors that impair AML-1 target gene expression. We demonstrated that the fusion proteins encoded by these translocations contact the nuclear hormone corepressors (N-CoR/SMRT), mSin3A, and histone deacetylases. We have also found that both TEL and AML-1 interact with mSin3A. TEL also binds N-CoR and histone deacetylase-3, indicating that wild-type TEL is a transcriptional repressor. The t(12;21) fuses the mSin3A interaction domain of TEL to AML-1 to transform AML-1 from a regulated to an unregulated transcriptional repressor. The recognition that AML-1 interacts with mSin3A to repress transcription suggested that the inv(16) fusion protein might also repress the transcription of AML-1-target genes. In fact, the inv(16) encodes a protein that cooperates with AML-1 to repress transcription. The inv(16) fusion protein was found in a ternary complex with AML-1 and mSin3A, suggesting that the inv(16) also acts by recruiting transcriptional corepressors and histone deacetylases.

3T3 Cells↗
PubMed2006

Cutaneous aneurysmal fibrous histiocytoma with a t(12;19)(p12;q13) as the sole cytogenetic anomaly.

We report a case of a 39-year-old woman with a recurrent aneurysmal fibrous histiocytoma of the right lower leg. Cytogenetic analysis of the tumor specimen disclosed a 46,XX,t(12;19)(p12;q13) karyotype. Multicolor fluorescence in situ hybridization (M-FISH), followed by conventional FISH analysis, confirmed the reciprocal translocation as the sole cytogenetic anomaly, and allowed for the positioning of chromosomes 12 and 19 breakpoints proximal to the BCL3 gene and between ETV6 and PIK3C2G gene loci, respectively. Our case highlights the importance of distinguishing this recurrent but benign lesion from similarly appearing malignant skin tumors. Cytogenetic analysis may contribute to the diagnosis of this uncommon but distinctive clinicopathological entity.

Adult↗
PubMed1998

Congenital mesoblastic nephroma t(12;15) is associated with ETV6-NTRK3 gene fusion: cytogenetic and molecular relationship to congenital (infantile) fibrosarcoma.

Morphological, cytogenetic, and biological evidence supports a relationship between congenital (infantile) fibrosarcoma (CFS) and congenital mesoblastic nephroma (CMN). These tumors have a very similar histological appearance, and they are both associated with polysomies for chromosomes 8, 11, 17, and 20. Recently, CFS was shown to contain a novel t(12; 15)(p13;q25) translocation resulting in ETV6-NTRK3 gene fusion. The aims of this study were to determine whether congenital mesoblastic nephroma contains the t(12;15)(p13;q25) translocation and ETV6-NTRK3 gene fusion and whether ETV6-NTRK3 fusions, in CMN and CFS, antedate acquisition of nonrandom chromosome polysomies. To address these aims, we evaluated 1) ETV6-NTRK3 fusion transcripts by reverse transcriptase polymerase chain reaction and sequence analysis, 2) genomic ETV6-region chromosomal rearrangement by fluorescence in situ hybridization, and 3) chromosomal polysomies by karyotyping and fluorescence in situ hybridization. We report ETV6-NTRK3 fusion transcripts and/or ETV6-region rearrangement in five of six CMNs and in five of five CFSs. The ETV6-NTRK3 fusion transcripts and/or ETV-region chromosome rearrangements were demonstrated in two CMNs and one CFS that lacked chromosome polysomies. These findings demonstrate that t(12;15) translocation, and the associated ETV6-NTRK3 fusion, can antedate acquisition of chromosome polysomies in CMN and CFS. CMN and CFS are pathogenetically related, and it is likely that they represent a single neoplastic entity, arising in either renal or soft tissue locations.

Artificial Gene Fusion↗
PubMed2002

Amifostine differentially modulates DNA damage evoked by idarubicin in normal and leukemic cells.

Human lymphocytes, p53 protein-deficient acute promyelocytic leukemia cell line HL-60, murine pro-B lymphoid cell line BaF3 and its TEL/ABL-transformed clone cells were exposed to idarubicin with and without pre-treatment with amifostine. Idarubicin at 0.5-5 microM evoked DNA damage measured by the Comet assay. Amifostine at 14 mM decreased DNA-damaging effect of idarubicin in human lymphocytes and BaF3 cells, but increased the effect in TEL/ABL-transformed cells. Amifostine had no influence on the action of idarubicin in HL-60 cells. Our results suggest that the reaction of the cell to DNA damage may contribute to its diverse response to amifostine combined with anticancer drugs and that p53 and fusion tyrosine kinases may be involved in this diversity.

Amifostine↗
PubMed1998

A novel variant of acute myelomonocytic leukemia carrying t(3;12)(q26;p13) with characteristics of 3q21q26 syndrome.

Chromosomal translocation often results in aberrant activation of the genes with oncogenic potential and, thus, plays an important role in leukemogenesis. We report a unique case of acute myelomonocytic leukemia carrying a rare reciprocal translocation, t(3;12)(q26;p13). This patient displayed typical clinical features of 3q21q26 syndrome such as abnormal thrombopoiesis and rapid disease progression. Blastic cells from the patient strongly expressed the EVI1 gene, which is located on 3q26 and is normally suppressed in bone marrow cells. Expression of the TEL gene, located on 12p13, was also observed, but fusion transcript between two genes was not found. No structural alterations of the EVI1 and TEL genes were detected by Southern blot and PCR analyses. We reviewed previous literature and found 10 other cases with t(3;12)(q26;p13). These patients comprise a unique disease group with features including dyshematopoiesis and poor prognosis. However, characteristics related to 3q21q26 syndrome were observed only in the present case. Further investigation is required to elucidate the molecular basis of this particular entity.

Chromosomes, Human, Pair 12↗
PubMed2001

ETV6 rearrangements in patients with infantile fibrosarcomas and congenital mesoblastic nephromas by fluorescence in situ hybridization.

Congenital mesoblastic nephroma (CMN) and infantile fibrosarcoma (IFS) are two pediatric tumors arising in the kidneys and soft tissues of infants, respectively. Recently, a t(12;15)(p13;q25) resulting in ETV6-NTRK3 gene fusion was detected in patients with IFS and in patients with the cellular type of CMN, suggesting a common pathogenetic pathway. We investigated the presence or absence of ETV6 rearrangements and numerical abnormalities of chromosome 11 by using fluorescence in situ hybridization on paraffin-embedded material from five cases of IFS, two of CMN, and one of mixed type (CMN and IFS) found in our files. In three cases of IFS, we found ETV6 gene rearrangement but a normal copy number of chromosome 11. One case each of IFS, the cellular type of CMN, and the mixed type (CMN and IFS) had both abnormalities. In a case of classic CMN, neither trisomy 11 nor gene rearrangement was found. It is possible that trisomy 11 is a later, nonessential event in the pathogenetic process or that this secondary aberration is associated with still-unrecognized clinical or biological characteristics. We confirmed that IFS and the cellular type of CMN are cytogenetically related and can occur synchronously in the same organ.

Child, Preschool↗
PubMed2002

A detailed transcriptional map of the chromosome 12p12 tumour suppressor locus.

Loss of heterozygosity of the short arm of chromosome 12 is a frequent event in a wide range of haematological malignancies and solid tumours. In previous studies, the shortest commonly deleted region was delimited to a 750-kb interval, defined by the markers D12S89 and D12S358, in pre-B acute lymphoblastic leukaemia patients, suggesting the presence of a tumour suppressor locus. Here we report the construction of a transcriptional map that integrates the data obtained by genomic sequence analysis, EST database search, comparative analysis and exon amplification. We identified seven putative transcriptional units as well as six pseudogenes. Four of these candidate genes were already known: ETV6, encoding an ets-like transcription factor, LRP6, a member of the LDL receptor gene family, BCL-G, a recently identified pro-apoptotic gene and MKP-7, encoding a new member of the dual-specificity phosphatase family. The products encoded by the three new genes identified in this study, LOH1CR12, LOH2CR12 and LOH3CR12, have no clear homology to known proteins. The gene predictions were all confirmed by expression analysis using RT-PCR and Northern blot. This transcriptional map is a crucial step toward the identification of the tumour suppressor gene at 12p12.

Algorithms↗
PubMed1997

Chromosome abnormalities of the short arm of chromosome 12 in hematopoietic malignancies: a report including three novel translocations involving the TEL/ETV6 gene.

A wide variety of abnormalities of the short arm of chromosome 12 has been reported in hematologic malignancies. The most frequent rearrangements result from t(12;21)(p13;q22) of childhood acute lymphoblastic leukemia, a translocation cryptic when leukemic cells are analyzed with chromosome banding techniques. This translocation results in a fusion of the TEL/ETV6 and AML1 genes. In this report, examples of rearrangements of 12p are presented. Study of two complex chromosome abnormalities associated with t(12;21) emphasizes the importance of using FISH in detection of such translocations. Three novel translocations involving the TEL/ETV6 gene localized on 12p13 are also reported: t(X;12)(q28;p13), t(1;12)(q21;p13), and t(9;12)(p23-24;p13). Finally, the presentation of two translocations with breakpoints located centromeric to TEL/ETV6 highlights the not uncommon involvement of genes other than TEL/ETV6 on 12p.

Adolescent↗