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Results for “ETS Translocation Variant 6 Protein”

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PubMed2002

Native interface of the SAM domain polymer of TEL.

BACKGROUND: TEL is a transcriptional repressor containing a SAM domain that forms a helical polymer. In a number of hematologic malignancies, chromosomal translocations lead to aberrant fusions of TEL-SAM to a variety of other proteins, including many tyrosine kinases. TEL-SAM polymerization results in constitutive activation of the tyrosine kinase domains to which it becomes fused, leading to cell transformation. Thus, inhibitors of TEL-SAM self-association could abrogate transformation in these cells. In previous work, we determined the structure of a mutant TEL-SAM polymer bearing a Val to Glu substitution in center of the subunit interface. It remained unclear how much the mutation affected the architecture of the polymer, however. RESULTS: Here we determine the structure of the native polymer interface. To accomplish this goal, we introduced mutations that block polymer extension, producing a heterodimer with a wild-type interface. We find that the structure of the wild-type polymer interface is quite similar to the mutant structure determined previously. With the structure of the native interface, it is possible to evaluate the potential for developing therapeutic inhibitors of the interaction. We find that the interacting surfaces of the protein are relatively flat, containing no obvious pockets for the design of small molecule inhibitors. CONCLUSION: Our results confirm the architecture of the TEL-SAM polymer proposed previously based on a mutant structure. The fact that the interface contains no obvious potential binding pockets suggests that it may be difficult to find small molecule inhibitors to treat malignancies in this way.

Biopolymers↗

PubMed2000

The TEL-AML1 fusion accompanied by loss of the untranslocated TEL allele in B-precursor acute lymphoblastic leukaemia of childhood.

The TEL-AML1 fusion which results from the t(12;21) rearrangement in childhood B-precursor acute lymphoblastic leukaemia (B-precursor ALL) is often accompanied by loss of the untranslocated TEL allele. From 32/109 children with B-precursor ALL screened for these abnormalities, we found evidence for del 12p, including the loss of the untranslocated TEL allele, to be the secondary event to take place in the leukaemic cells from those patients positive for these abnormalities. This suggests that the initial or predisposing event is the generation of a TEL-AML1 fusion, followed by the promoting event of a deletion of a gene(s) on 12p. A striking characteristic of the leukaemic cells in 61% of the patients showing t(12:21). was the substantial evolution of the primary clonal line containing the reciprocal TEL-AML1 fusion. We were able to show loss of normal TEL in the same patients by interphase fluorescence in situ hybridisation (FISH) analysis and reverse-transcriptase polymerase chain reaction (RT-PCR).

Alleles↗

PubMed2005

Infantile fibrosarcoma of thigh--a case report.

Infantile fibrosarcoma is a rare soft tissue malignant tumor, when it occurs, it is usually seen in the first year of life. The clinical course of infantile fibrosarcoma is more favorable and metastasis is rare compared with that in adulthood. While adult fibrosarcoma are common in the thigh, infantile fibrosarcoma affect chiefly the distal portions of the extremities. Standard treatment is primarily wide surgical excision. In this case report, we present our experience of an infantile fibrosarcoma of thigh with good clinical course 36 months after tumor resection and the usefulness of detecting the ETV6-NTRK3 gene fusion in differential diagnosis.

DNA-Binding Proteins↗

PubMed2001

The chimeric protein tyrosine kinase ETV6-NTRK3 requires both Ras-Erk1/2 and PI3-kinase-Akt signaling for fibroblast transformation.

There is increasing interest in the potential role of the NTRK family of neurotrophin receptors in human neoplasia. These receptor protein tyrosine kinases (PTKs) are well-known mediators of neuronal cell survival and differentiation, but altered NTRK signaling has also been implicated in mesenchymal, hematopoietic, and epithelial malignancies. We recently identified a novel gene fusion involving one of the neurotrophin receptor genes, NTRK3, in the pediatric solid tumor, congenital fibrosarcoma. In these tumors (and subsequently demonstrated in several other human malignancies), a t(12;15)(p13;q25) rearrangement fuses the 3' portion of the ETV6 gene with exons encoding the PTK domain of NTRK3. The resulting ETV6-NTRK3 fusion protein functions as a chimeric PTK with potent transforming activity. However, previous studies failed to detect interactions between ETV6-NTRK3 and molecules known to link wild-type NTRK3 to its two major effector pathways, namely the Ras-Raf1-Mek1-Erk1/2 mitogenic pathway or the phosphatidylinositol 3'-kinase pathway leading to activation of the AKT survival factor. Therefore, it remains unknown whether ETV6-NTRK3 transformation involves altered NTRK3 signaling. We now report that ETV6-NTRK3 expression in NIH3T3 cells leads to constitutive activation of Mek1 and Akt, as well as to constitutively high expression of cyclin D1. ETV6-NTRK3-induced soft agar colony formation was almost completely abolished by inhibition of either the Ras-Raf1-Mek1-Erk1/2 or the phosphatidylinositol 3'-kinase-Akt pathway. Moreover, this inhibition dramatically reduced expression of cyclin D1. Our results indicate that ETV6-NTRK3 transformation involves a link between known NTRK3 signaling pathways and aberrant cell cycle progression and that Mek1 and Akt activation act synergistically to mediate these effects.

3T3 Cells↗

PubMed1995

TEL and KIP1 define the smallest region of deletions on 12p13 in hematopoietic malignancies.

Unbalanced translocations as well as interstitial deletions of the short arm of chromosome 12 [del(12p)] are found as recurring chromosomal changes in a broad spectrum of hematopoietic malignancies. These changes result in the hemizygous deletion of genetic material from 12p. We mapped a yeast artificial chromosome containing the TEL gene, a cosmid contig containing part of TEL and a P1 contig containing the KIP1 gene to 12p13. These probes were used for fluorescence in situ hybridization to analyze samples from 47 patients with various hematologic malignancies who had unbalanced translocations (25 patients) leading to loss of 12p or deletions (22 patients) involving 12p13. The patients had acute lymphoblastic leukemia (8 cases), myelodysplastic syndrome (MDS; 11 cases), acute myeloid leukemia (AML; 10 cases), myeloproliferative disorders (4 cases), therapy-related MDS or AML (7 cases), non-Hodgkin's lymphoma (2 cases), and other hematopoietic malignancies (5 cases). All three probes were hemizygously detected in 26 cases and were completely retained in only 9 cases. In 12 cases probes for one of the two genes were deleted, allowing us to map the smallest region of overlap of these deletions to a small genomic region that is bordered on the telomeric side by the TEL gene and on the centromeric side by KIP1. The genomic distance between TEL and KIP1 is estimated to be about 1 to 2 Mbp.

Adolescent↗

PubMed1995

Frequent loss of heterozygosity at the TEL gene locus in acute lymphoblastic leukemia of childhood.

TEL is a new member of the ETS family of transcription factors which is rearranged in a number of hematologic malignancies with translocations involving chromosome band 12p13. In some cases, both TEL alleles are affected, resulting in loss of wild-type TEL function in the leukemic cells. In addition, 5% of children with acute lymphoblastic leukemia (ALL) have 12p12-p13 deletions, suggesting that a tumor suppressor gene resides on 12p. These observations led us to consider whether TEL loss of function may contribute to the pathogenesis of ALL. In this report we show that the TEL gene maps between the polymorphic markers D12S89 and D12S98, and we use these flanking markers to screen paired diagnosis and remission samples from 81 children with ALL for loss of heterozygosity (LOH) at the TEL gene locus. Fifteen percent of informative patients showed TEL LOH which was not evident on cytogenetic analysis. Detailed examination of patients with LOH at this locus showed that the critically deleted region included two candidate tumor suppressor genes: TEL and KIP1, the gene encoding the cyclin-dependent kinase inhibitor p27. These studies show that LOH at the TEL locus is a frequent finding in childhood ALL.

Adolescent↗

PubMed1996

Acute lymphoblastic leukemia of childhood: identification of two distinct regions of deletion on the short arm of chromosome 12 in the region of TEL and KIP1.

Cytogenetic analysis of acute lymphoblastic leukemia (ALL) of childhood identified nonrandom chromosomal abnormalities of the short arm of chromosome 12. The alterations include deletions that are thought to be indicative of the presence of a tumor suppressor gene that is mutated on the remaining allele. To refine further the chromosomal localization of this gene, we analyzed the loss of heterozygosity (LOH) of chromosome 12 in 100 primary ALL samples using 22 polymorphic markers and identified two distinct smallest common deleted regions on chromosome 12p13. One region is flanked by D12S77 and D12S98 and has a size of 4 cM. Twenty-six percent of informative patients showed LOH in this region. This region may contain the TEL gene. The other region is flanked by D12S269 and D12S308 including the KIP1 gene. Forty-four percent of informative patients showed LOH in this second region. Mutational analysis of KIP1 using polymerase chain reaction-single-strand conformation polymorphism analysis and Southern blot analysis showed no homozygous deletions and point mutations suggesting that the altered gene in this second region is not the KIP1. Clinical data showed that LOH of 12p was demonstrated more frequently in precursor-B ALLs (32 of 80; 40%) than in T-ALLs (1 of 20; 5%) (P = .0027). Furthermore, patients with 12p LOH were younger (P = .013), with a lower DNA index (P = .046), but they had the same survival rates at 3 years. In summary, these data suggest that two different tumor suppressor genes are on chromosome arm 12p, which act separately in the development of childhood precursor-B ALLs. One of the tumor suppressor genes is in the region the KIP1 gene, but our data suggest this gene is not abnormal. The other target is in the region of the TEL gene; and this candidate deserves further study.

Cell Cycle Proteins↗

PubMed2005

Somatic heterozygous mutations in ETV6 (TEL) and frequent absence of ETV6 protein in acute myeloid leukemia.

ETV6 (ets translocation variant gene 6) TEL (translocation ets leukemia), encoding a transcriptional repressor, is involved in various translocations associated with human malignancies. Strikingly, the nonrearranged ETV6 allele is often deleted or inactivated in cells harboring these translocations. Although ETV6 translocations are infrequent in acute myeloid leukemia (AML), mutations or deregulated expression of ETV6 may contribute to leukemogenesis. To investigate the involvement of ETV6 in AML, we analysed 300 newly diagnosed patients for mutations in the coding region of the gene. Furthermore, we studied protein expression in 77 patients using two ETV6-specific antibodies. Five somatic heterozygous mutations were detected, which affected either the homodimerization- or the DNA-binding domain of ETV6. The proteins translated from the cDNAs of these mutants were unable to repress transcription and showed dominant-negative effects. In addition, we demonstrate that one-third of AML patients have deficient ETV6 protein expression, which is not related to ETV6 mRNA expression levels. In conclusion, we demonstrate that ETV6 abnormalities are not restricted to translocations and occur more frequently in AML than previously thought. Additional comprehensive studies are required to define the clinical consequence of ETV6 loss of function in AML.

Acute Disease↗

PubMed2005

Molecular cytogenetic characterization of rearrangements involving 12p in leukemia.

Translocations involving the short arm of chromosome 12 are frequent events among patients with various hematologic malignancies. In approximately half of these patients, fluorescence in situ hybridization (FISH) analysis has shown that the breakpoints are clustered within the ETS-variant gene 6 (ETV6) at 12p13, leading to its fusion with a variety of partner genes on different chromosomes. The remaining patients have breakpoints centromeric or telomeric to ETV6 or, less frequently, interstitial 12p13 deletions that invariably involve this gene. In most cases reported, 12p translocations were found to be associated with other structural and/or numerical abnormalities as part of a complex karyotype. Initially using conventional cytogenetic analysis, we characterized the chromosomal breakpoints of three leukemia patients (two with B-acute lymphoblastic leukemia and one with myelodysplastic/myeloproliferative disorder) presenting a t(5;12)(q13;p13), t(12;15)(p13;q22), and dic(9;12)(p11;p11), respectively, as the only structural abnormalities in the karyotype. These rearrangements were further investigated using FISH and molecular studies. Two cases revealed cryptic three-way translocations that had gone undetected in the conventional cytogenetic analyses. One of the cases presented an ETV6 rearrangement with an unsuspected fusion, with the CBFA2 gene at 21q22. In the other two, small and large 12p deletions that included ETV6 were found. This report illustrates the chromosomal and molecular heterogeneity of rearrangements underlying 12p chromosome translocations in leukemia.

Aged↗

PubMed2003

A novel cryptic translocation t(12;17)(p13;p12-p13) in a secondary acute myeloid leukemia results in a fusion of the ETV6 gene and the antisense strand of the PER1 gene.

The ETV6 gene is a member of the ETS family of transcription factors and the main target of chromosomal rearrangements affecting chromosome band 12p13. To date, more than 15 fusion partners of ETV6 have been characterized at the molecular level. Most of these fusions encode chimeric proteins with oncogenic properties. However, some of the translocations do not produce a functional fusion protein, but may induce ectopic expression of oncogenes located close to the breakpoint. We herein report the characterization and cloning of a novel cryptic translocation, t(12;17)(p13;p12-p13), occurring in a patient with an acute myeloid leukemia evolving from a chronic myelomonocytic leukemia. Cytogenetic analysis suggested the presence of a deletion of the short arm of chromosome 12, del(12)(p13), in three of the five metaphase cells analyzed. However, fluorescence in situ hybridization (FISH) with the ETV6-specific cosmid clones 179A6, 50F4, 163E7, and 148B6 as well as probes hybridizing to the TP53 gene on 17p13 and the subtelomeric region of 17p revealed the presence of a translocation between 12p and 17p. By FISH, the breakpoints could be localized in intron 1 of ETV6 and centromeric to TP53. By 3' rapid amplification of cDNA ends-polymerase chain reaction (3' RACE-PCR), a fusion transcript between exon 1 of ETV6 and the antisense strand of PER1 (period homolog 1, Drosophila), a circadian clock gene, could be identified. This ETV6-PER1 (antisense PER1 strand) fusion transcript does not produce a fusion protein, and no other fusion transcripts could be detected. We hypothesize that in the absence of a fusion protein, the inactivation of PER1 or deregulation of a gene in the neighborhood of PER1 may contribute to the pathogenesis of leukemias with a t(12;17)(p13;p12-p13).

Acute Disease↗

PubMed2003

Heterogeneity of the 7q36 breakpoints in the t(7;12) involving ETV6 in infant leukemia.

The t(7;12)(q36;p13) is a recurrent chromosome abnormality in infant leukemia. In these cases, the involvement of ETV6, with disruption of the gene consistently at its 5' end, has been reported by several groups. A fusion transcript between ETV6 and HLXB9 has been detected in some, but not all, reported cases of t(7;12). We report here a study based on fluorescence in situ hybridization (FISH) mapping of the translocation breakpoints in seven patients and detailed molecular studies using Southern blotting on two of these patients. The FISH studies have shown a cluster of breakpoints within a cosmid contig proximal to the HLXB9 gene. Southern blotting analysis enabled us to define two distinct breakpoints within the area covered by the cosmid contig in two patients. The analysis of an unusual case of t(7;12)(q22;p13) [full karyotype: 46,XX,der(7)t(7;12)(q22;p13)del(7)(q22q36)] also revealed a break in 7q36, although in a region proximal to the overlapping cosmids. 5' RACE PCR in one patient has shown a rearrangement involving the ETV6 allele not involved in the t(7;12), suggesting that no functional ETV6 allele might be present in this case. These data show some heterogeneity in the distribution of breakpoints in 7q36, indicating that the generation of a fusion gene might not be the mechanism responsible for leukemogenesis in the t(7;12), at least in some cases.

Base Sequence↗

PubMed2005

ETV6 gene rearrangements in invasive breast carcinoma.

The ETV6/TEL gene encodes a transcription factor frequently rearranged in several types of cancer. We looked for ETV6 rearrangements in invasive breast cancer using fluorescence in situ hybridization (FISH) of BAC probes on sections of tissue microarrays containing 632 tumor samples. Of these samples, signal of sufficient quality for screening by FISH was obtained for 356. Five cases (one lobular, one nontypical secretory, one mixed, and two ductal carcinomas) showed ETV6 rearrangement.

Adenocarcinoma↗

PubMed2004

Expression cloning of oligomerization-activated genes with cell-proliferating potency by pseudotype retrovirus vector.

We developed a method of clone proliferation promoting fusion genes whose proteins were activated by protein oligomerization through the helix-loop-helix region (PNT domain) of TEL. We inserted a cDNA library downstream of the PNT domain with a retrovirus vector. The resulting retrovirus infected cytokine-dependent 32D cells and cells with cytokine-independent growth were analyzed for the inserted cDNA. We cloned 25 independent fusion genes including seven kinds of partner genes. Six of the seven were a fusion of TEL with protein tyrosine kinase, LYN, HCK, FGR, SYK, FLT3, and TYK2. A serine/threonine kinase, ARAF1, was also found to fuse with TEL. These kinase fusion proteins included kinase domains with proper reading frames. These fusions may be a useful model for clarifying the downstream signal transduction of constitutive active kinase and this expression cloning method may provide a new tool with which to study cell proliferation signalling.

Animals↗

PubMed2006

TEL/ETV6 induces apoptosis in 32D cells through p53-dependent pathways.

TEL is an ETS family transcription factor that is critical for maintaining hematopoietic stem cells in adult bone marrow. To investigate the roles of TEL in myeloid proliferation and differentiation, we introduced TEL cDNA into mouse myeloid 32Dcl3 cells. Overexpression of TEL repressed interleukin-3-dependent proliferation through blocking cell cycle progression. Also, the presence of TEL triggered apoptosis through the mitochondrial intrinsic pathway on exposure to granulocyte colony-stimulating factor. We found an increase in p53 protein and its DNA binding in the TEL-overexpressing cells. Forced expression of TEL stimulated transcription via the p53-responsive element and increased the expression of cellular target genes for p53 such as cell cycle regulator p21 and apoptosis inducer Puma. Consistently, induction of apoptosis was delayed by pifithrin-alpha treatment and completely blocked by increased expression of Bcl-2 in the TEL-overexpressing cells. These data collectively suggest that TEL exerts a tumor suppressive function through augmenting the p53 pathway and facilitates normal development of myelopoiesis.

Animals↗

PubMed2005

Detection of ETV6 and RUNX1 gene rearrangements using fluorescence in situ hybridization in Mexican patients with acute lymphoblastic leukemia: experience at a single institution.

The t(12;21) produces the gene fusion ETV6/RUNX1 and is a frequent rearrangement in childhood ALL, associated with a good prognosis. In Mexico its prevalence has not been reported. This study evaluated a group of consecutive Mexican children with newly diagnosed ALL, to detect the fusion using fluorescence in situ hybridization (FISH). Seventy-one bone marrow samples were analyzed with FISH, using ETV6/RUNX1 DNA probes. Abnormalities of ETV6, RUNX1, or both were found in 31 of the 71 (44%) patients. Six showed ETV6/RUNX1 fusion and 17, with extra RUNX1 copies, presented an additional chromosome 21 or dup(21)(q22). Five patients had structural changes in ETV6, and three patients showed extra copies of ETV6 and RUNX1 from polysomy of chromosomes 12 and 21. Our results revealed a fusion in 8.5% of the 71 cases analyzed. This frequency is lower than that observed in other populations (9.5-32%). The structural rearrangements resulting in RUNX1 extra copies were found in 9.8% of patients, which is close to the range reported (1.5-9.7%) by other authors. Due to the prevalence of RUNX1 overrepresentation in our population and its unknown prognostic significance, further studies should be conducted in consecutive children with ALL, to correlate this abnormality with the patients' follow-up.

Adolescent↗

PubMed2006

A t(12;17)(p13;q12) identifies a distinct TEL rearrangement-negative subtype of precursor-B acute lymphoblastic leukemia.

Structural rearrangements involving the short arm of chromosome 12 are common in acute lymphoblastic leukemia (ALL) and often involve the TEL locus at 12p13. The balanced t(12;17)(p13;q12) is a rare but recurrent aberration in ALL. Whereas the TEL gene has been postulated as a likely candidate for involvement in the t(12;17), the precise molecular consequences of this translocation have not yet been elucidated. We identified a t(12;17) in 2 of 398 childhood ALL patients karyotyped at presentation in our institute. Both cases had a precursor-B immunophenotype and were CD10 negative and CD33 positive. Fluorescence in situ hybridization excluded involvement of the TEL locus in the t(12;17) and provided no evidence for concomitant cryptic deletion of the 12p commonly deleted region. Comparison of these and previously published cases demonstrates that the translocation predominately occurs in children and young adults with precursor B-ALL and is typically characterized by low CD10 expression and high CD33 expression. Our data support the involvement of a new locus telomeric to TEL in the pathogenesis of t(12;17)-positive ALL.

Adolescent↗

PubMed2005

Hematopoietic perturbation in zebrafish expressing a tel-jak2a fusion.

OBJECTIVE: Various TEL-JAK2 fusions have been identified in patients with lymphoblastic and myeloid leukemias that result in constitutive activation of the JAK2 kinase domain. Such fusions can mediate factor-independent growth of hematopoietic cell lines and induction of malignancy in mouse models. MATERIALS AND METHODS: To assess whether zebrafish could be utilized as a suitable model for the study of myeloid oncogenesis, we generated a zebrafish tel-jak2a fusion oncoprotein based on that seen in a case of chronic myeloid leukemia. This was transiently expressed in zebrafish embryos under the control of the spi1 promoter, which is strongly active in myeloid precursors. RESULTS: Visual, histological, and molecular analysis revealed disruption of normal embryonic hematopoiesis, including perturbation of the myeloid and erythroid lineages. CONCLUSION: These results indicate that the zebrafish tel-jak2a oncoprotein is functional, and suggest that this organism will be useful for the experimental study of myeloid malignancy.

Acute Disease↗

PubMed2005

HLA-DM expression is elevated in ETV6-AML1 translocation-positive pediatric acute lymphoblastic leukemia.

MHC Class II antigen processing and presentation to CD4+ T cells is important in anti-tumor immunity. ETV6-AML1-positive precursor-B acute lymphoblastic leukemia (pre-B ALL) is associated with good outcome and late relapse. We analyzed HLA-DR and the MHC Class II processing components HLA-DO, HLA-DM, and Class II-associated invariant chain peptide (CLIP) expression, in ETV6-AML1-positive and ETV6-AML1-negative ALL. Overall, CLIP expression was low, while HLA-DM was significantly higher in ETV6-AML1-positive cells. No significant difference in HLA-DO was observed. The HLA-DR(high)/CLIP(low)/HLA-DM(high) phenotype strongly suggests that ETV6-AML1 leukemia will induce favorable immune responses and may in part explain the characteristic late relapses associated with ETV6-AML1 pre-B ALL.

Child↗