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PubMed1999

TEL/PDGFbetaR induces hematologic malignancies in mice that respond to a specific tyrosine kinase inhibitor.

The TEL/PDGFbetaR fusion protein is expressed as the consequence of a recurring t(5;12) translocation associated with chronic myelomonocytic leukemia (CMML). Unlike other activated protein tyrosine kinases associated with hematopoietic malignancies, TEL/PDGFbetaR is invariably associated with a myeloid leukemia phenotype in humans. To test the transforming properties of TEL/PDGFbetaR in vivo, and to analyze the basis for myeloid lineage specificity in humans, we constructed transgenic mice with TEL/PDGFbetaR expression driven by a lymphoid-specific immunoglobulin enhancer-promoter cassette. These mice developed lymphoblastic lymphomas of both T and B lineage, demonstrating that TEL/PDGFbetaR is a transforming protein in vivo, and that the transforming ability of this fusion is not inherently restricted to the myeloid lineage. Treatment of TEL/PDGFbetaR transgenic animals with a protein tyrosine kinase inhibitor with in vitro activity against PDGFbetaR (CGP57148) resulted in suppression of disease and a prolongation of survival. A therapeutic benefit was apparent both in animals treated before the development of overt clonal disease and in animals transplanted with clonal tumor cells. These results suggest that small-molecule tyrosine kinase inhibitors may be effective treatment for activated tyrosine kinase-mediated malignancies both early in the course of disease and after the development of additional transforming mutations.

Animals↗
PubMed1999

Fusion of a novel gene, BTL, to ETV6 in acute myeloid leukemias with a t(4;12)(q11-q12;p13).

The ETV6 gene (also known as TEL) is the main target of chromosomal translocations affecting chromosome band 12p13. The rearrangements fuse ETV6 to a wide variety of partner genes in both myeloid and lymphoid malignancies. We report here 4 new cases of acute myeloid leukemia (AML) with very immature myeloblasts (French-American-British [FAB]-M0) and with a t(4;12)(q11-q12;p13). In all cases, ETV6 was found recombined to a new gene, homologous to the mouse Brx gene. The gene was named BTL (Brx-like Translocated in Leukemia). Reverse transcriptase-polymerase chain reaction (RT-PCR) experiments indicate that the expression of the BTL-ETV6 transcript, but not of the reciprocal ETV6-BTL transcript, is a common finding in these leukemias. In contrast to the majority of other ETV6 fusions, both the complete helix-loop-helix (HLH) and ETS DNA binding domains of ETV6 are present in the predicted BTL-ETV6 fusion protein, and the chimeric gene is transcribed from the BTL promoter.

Acute Disease↗
PubMed2000

Recruitment of the nuclear receptor corepressor N-CoR by the TEL moiety of the childhood leukemia-associated TEL-AML1 oncoprotein.

The t(12;21)(p13;q22) chromosomal translocation is the most frequent illegitimate gene recombination in a pediatric cancer and occurs in approximately 25% of common acute lymphoblastic leukemia (cALL) cases. This rearrangement results in the in frame fusion of the 5'-region of the ETS-related gene, TEL (ETV6), to almost the entire acute myeloid leukemia 1 (AML1) (also called CBFA2 or PEBP2AB1) locus and expression of the TEL-AML1 chimeric protein. Although AML1 stimulates transcription, TEL-AML1 functions as a repressor of some AML1 target genes. In contrast to the wild type AML1 protein, both TEL and TEL-AML1 interact with N-CoR, a component of the nuclear receptor corepressor complex with histone deacetylase activity. The interaction between TEL and N-CoR requires the central region of TEL, which is retained in TEL-AML1, and TEL lacking this domain is impaired in transcriptional repression. Taken together, our results suggest that TEL-AML1 may contribute to leukemogenesis by recruiting N-CoR to AML1 target genes and thus imposing an altered pattern of their expression.

Core Binding Factor Alpha 2 Subunit↗
PubMed2001

[The role of TEL and AML1 genes in the pathogenesis of hematologic malignancies].

TEL and AML1 genes occur in a markedly high number of different aberrations in haematological malignancies. Besides the AML1, TEL is often fused to genes, which encod thyrosin-kinases. AML1 gene is a part of CBF transcription factor. AML1 can be altered in childhood acute lymphoblastic leukaemia (ALL) and also in a substantial number of acute myeloid leukaemias (most frequently as an AML1/ETO fusion). TEL/AML1 fusion gene (derived from t(12;21)(p13;q22) translocation) became recently one of the most important genetic aberrations in children with ALL. TEL/AML1 act presumably as dominant inhibitors of the second AML1 allele and thus they block transcription of genes dependent on CBF factor. Childhood ALL with TEL/AML1 hybrid gene is very frequent (approximately 22% of overall childhood ALL in the Czech Republic) and patients with this fusion form relatively homogenous group. These children are diagnosed mostly in pre-school age as a B cell precursor leukaemias and they have very good treatment results.

Animals↗
PubMed2002

TEL-JAK2 constitutively activates the extracellular signal-regulated kinase (ERK), stress-activated protein/Jun kinase (SAPK/JNK), and p38 signaling pathways.

The ets transcription factor, TEL, undergoes chromosomal rearrangements with the tyrosine kinase JAK2. TEL-JAK2 is constitutively active, confers cell line factor independence, and activates signal transducer and activator of transcription-1 (STAT1), STAT3, and STAT5. Data from bone marrow transplantation models suggest that STAT5 activation does not account for the entire disease phenotype induced by TEL-JAK2. This study examined additional signaling pathways that are activated by TEL-JAK2. TEL-JAK2 expression in Ba/F3 cells results in constitutive association and tyrosine phosphorylation of Shc and Ship-1 and, consequently, recruitment of Grb2 to TEL-JAK2. Direct Grb2 recruitment is also possible because a putative Grb2 binding site, Tyr314, is present on TEL-JAK2(5-19) and TEL-JAK2(5-12). Studies with a TEL-JAK2(5-19)Tyr314Phe mutant support a role for Tyr314 in Grb2 recruitment, because Grb2 association with TEL-JAK2(5-19)Tyr314Phe is significantly reduced. Interestingly, TEL-JAK2(5-19)Tyr314Phe shows reduced Ras activation when compared with TEL-JAK2(4-17), TEL-JAK2(5-12), and TEL-JAK2(5-19). Analysis of extracellular signal-regulated kinase-1/2 (ERK1/2), stress-activated protein/Jun kinase (SAPK/JNK), and p38 demonstrates the activation of SAPK/JNK and phosphorylation of p38 by all TEL-JAK2 isoforms. TEL-JAK2(5-12) and TEL-JAK2(5-19) preferentially phosphorylate ERK2, whereas TEL-JAK2(4-17) phosphorylated ERK2 at lower levels. Inhibition studies demonstrated that ERK1/2 activation was necessary for Ba/F3 factor independence mediated by TEL-JAK2(5-19), while inhibition of SAPK/JNK or p38 activity had no effect. Our data reveal the requirement of ERK activation by TEL-JAK2(5-19) in Ba/F3 cells and suggest that TEL-JAK2 leukemogenic potential may be mediated in part through ERK1/2.

Adaptor Proteins, Signal Transducing↗
PubMed2004

TEL/AML1 overcomes drug resistance through transcriptional repression of multidrug resistance-1 gene expression.

The t(12;21)(p12;q22) chromosomal aberration, which is frequently observed in pediatric precursor B-cell acute lymphoblastic leukemia (ALL), generates the TEL/AML1 chimeric gene and protein. TEL/AML1-positive ALL has a favorable prognosis, and one possible reason is that this subtype of ALL rarely shows drug resistance. AML1/ETO, another AML1-containing chimeric protein, has been shown to transcriptionally repress the activity of the multidrug resistance-1 (MDR-1) gene promoter; thus, we examined whether TEL/AML1 also represses MDR-1 gene expression, possibly preventing the emergence of multidrug resistance. In this study, we show that the TEL/AML1 protein binds to the consensus AML1 binding site in the MDR-1 promoter and transcriptionally represses its activity. Following transient transfection of TEL/AML1 protein into Adriamycin-resistant K562/Adr cells, we also demonstrate that TEL/AML1 can down-regulate the expression of P-glycoprotein, a product of the MDR-1 gene, and restore the chemosensitivity to the cells. Furthermore, we report that MDR-1 mRNA levels in leukemic cells obtained from TEL/AML1-positive ALL patients are lower than those from TEL/AML1-negative ALL patients. Thus, TEL/AML1 protein acts as a transcriptional repressor of MDR-1 gene expression, and although TEL/AML1 has been implicated in leukemogenesis, its effects on the MDR-1 gene may contribute to the excellent prognosis of TEL/AML1-positive ALL with current therapy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

High frequency of t(12;21) in childhood B-lineage acute lymphoblastic leukemia.

The recurrent t(12;21)(p12;q22) translocation fuses two genes, TEL and AML1, that have previously been shown to be independently involved in myeloid malignant proliferations. A search for rearrangement of the TEL locus in the region known to be involved in t(12;21) was performed by Southern blotting in a panel of hematopoietic malignancies. The presence of a t(12;21) was confirmed by fluorescence in situ hybridization (FISH) and/or reverse transcriptase (RT)-polymerase chain reaction (PCR). We report that fusion of TEL to AML1 is specifically observed in at least 16% of the childhood B-lineage acute lymphoblastic leukemia (ALL) investigated, none of which had been previously identified as harboring t(12;21).

Adolescent↗
PubMed1995

Translocation (12;22) (p13;q11) in myeloproliferative disorders results in fusion of the ETS-like TEL gene on 12p13 to the MN1 gene on 22q11.

In myeloid and lymphoid leukemias recurrent chromosomal aberrations can be detected in chromosome region 12p13. We characterized the genes involved in t(12;22) (p13;q11) in two patients with myeloid leukemia and one with myelodysplastic syndrome (MDS). MN1, a gene on chromosome 22q11 was shown to be fused to TEL, a member of the family of ETS transcription factors on chromosome 12p13. The translocation results in transcription of the reciprocal fusion mRNAs, MN1-TEL and TEL-MN1, of which MN1-TEL is likely to encode an aberrant transcription factor containing the ETS DNA-binding domain of TEL. In addition to fusion of TEL to the PDGF beta receptor in t(5;12) in chronic myelomonocytic leukemia (CMML), our data suggest that the involvement of this protein in myeloid leukemogenesis could be dual; its isolated protein-protein dimerization and DNA-binding domains may be crucial for the oncogenic activation of functionally different fusion proteins.

Adult↗
PubMed1995

TEL gene is involved in myelodysplastic syndromes with either the typical t(5;12)(q33;p13) translocation or its variant t(10;12)(q24;p13).

A t(5;12)(q33;p13) translocation is a recurrent chromosome abnormality in a subgroup of myeloid malignancies with features of both myeloproliferative disorders and myelodysplastic syndromes (MDSs). The molecular consequence of a t(5;12) is a fusion between the platelet-derived growth factor receptor-B gene on chromosome 5 and a novel ETS-like gene, TEL, on chromosome 12. We report on three patients with a t(5;12)(q33;p13) diagnosed as chronic myelomonocytic leukemia, and one case of a t(10;12)(q24;p13) in a progressive MDS, with eosinophilia and monocytosis. Involvement of the TEL gene in these chromosome translocations was investigated by fluorescence in situ hybridization (FISH) with cosmid probes containing selectively the 5' end or 3' end of TEL. Hybridization of these cosmids to the der(5)/der(10) or a der(12), respectively, demonstrated a rearrangement of TEL in both translocations, showing that the t(10;12) is a variant translocation of the t(5;12). Cloning of the fusion cDNA of one case of t(5;12) showed that the breakpoint occurred at the RNA level at exactly the same position as reported by Golub et al (Cell 77:307, 1994). In addition, the TEL gene on chromosome 12 could be localized between two probes previously mapped to 12p13, namely PRB1 and D12S178, leading to a better definition of the position of TEL in this chromosome region. Moreover, in the case involving chromosome 10, the breakpoint occurred between cKTN206 and cKTN312/LYT-10 at 10q24. Clinicohematological data in these studies as well as the restriction mapping of chromosomal breakpoints strongly suggest that (1) common features in MDSs involving the TEL gene are monocytosis and eosinophilia, (2) chromosomes other than no. 5 may be involved and at least a t(10;12)(q24;p13) variant chromosome translocation does exist in these MDSs, and (3) both standard and variant 12p/TEL translocations may be identified by FISH with appropriate probes.

Adult↗
PubMed1995

The t(12;21) of acute lymphoblastic leukemia results in a tel-AML1 gene fusion.

Analysis of a growing number of chromosomal translocations in human tumors have shown that they frequently result in gene fusions encoding chimeric proteins. We have characterized the recurrent t(12;21)(p12;q22) translocation present in human B-lineage acute leukemias. This translocation fused two genes, tel and AML1, that have previously been described in chromosomal translocations specific for myeloid malignancies. These two genes therefore belong to an increasing number of human genes that are involved in a variety of hematopoietic malignant disorders and can be rearranged with numerous partners. Interestingly, in these acute leukemias, deletion of the other tel allele from the normal chromosome 12 was associated with the tel rearrangement, whereas both tel alleles were present in the chronic leukemias bearing a t(5;12) that we have tested.

Adolescent↗
PubMed1995

TEL/AML1 fusion resulting from a cryptic t(12;21) is the most common genetic lesion in pediatric ALL and defines a subgroup of patients with an excellent prognosis.

The t(12;21)(p13;q22) is identified by routine cytogenetics in less than 0.05% of pediatric acute lymphoblastic leukemia (ALL) patients. This translocation encodes a TEL/AML-1 chimeric product comprising the helix-loop-helix domain of TEL, a member of the ETS-like family of transcription factors, fused to AML-1, the DNA-binding subunit of the AML-1/CBF beta transcription factor complex. Both TEL and AML-1 are involved in several myeloid leukemia-associated translocations with AML-1/CBF beta being altered in 20-30% of de novo acute myeloid leukemia (AML) cases. We now demonstrate that a TEL/AML1 chimeric transcript encoded by a cryptic t(12;21) is observed in 22% of pediatric ALL, making it the most common genetic lesion in these patients. Moreover, TEL/AML1 expression defined a distinct subgroup of patients characterized by an age between 1 and 10 years, B lineage immunophenotype, non-hyperdiploid DNA content and an excellent prognosis. These data demonstrate that molecular diagnostic approaches are invaluable in identifying clinically distinct subgroups, and that the AML1/CBF beta transcription complex is the most frequent target of chromosomal rearrangements in human leukemia.

Base Sequence↗
PubMed1996

The 12;21 translocation involving TEL and deletion of the other TEL allele: two frequently associated alterations found in childhood acute lymphoblastic leukemia.

A recurrent t(12;21)(p13;q22) has recently been described in human acute lymphoblastic leukemias (ALLs). This translocation fuses TEL and AML1, two genes previously cloned from translocation breakpoints in myeloid leukemias. In addition, allelic loss of the TEL gene can be detected in 15% to 22% of childhood ALLs. In the present study, we have sought allelic deletions of TEL and the presence of the t(12;21) in 50 children with B-lineage ALL, using a combination of microsatellite typing, fluorescent in situ hybridization (FISH), and analysis of the fusion transcripts resulting from the TEL-AML1 gene fusion. Our results indicate that the association between the t(12;21) and the deletion of the nontranslocated allele of TEL is among the most frequent abnormalities observed in B-lineage ALLs. FISH analysis using several cosmid probes showed that, in one patient with a t(12;21) translocation involving TEL, the second allele had an intragenic deletion. This observation points to TEL as the actual target of 12p12-13 deletions in patients that associate a t(12;21) with a deletion. The TEL-AML1 fusion RNA was found in all patients with the t(12;21) whereas the reciprocal AML1-TEL transcript was only found in a subset of patients, suggesting that only the protein product encoded by TEL-AML1 is likely to play a role in leukemogenesis. The observation that, in two patients with the t(12;21), a deletion of TEL was only present in a subclone indicates that this deletion was a secondary event that occurred after the translocation. The frequent occurrence of TEL deletions in patients with t(12;21) suggests that the deletion of the normal TEL allele subsequent to the t(12;21) provides a further proliferative advantage to leukemic cells.

Adolescent↗
PubMed1996

Fluorescence in situ hybridization analysis of t(3; 12)(q26; p13): a recurring chromosomal abnormality involving the TEL gene (ETV6) in myelodysplastic syndromes.

We have identified a new recurrent reciprocal translocation between chromosome 3 and 12 with breakpoints at bands 3q26 and 12p13, t(3;12)(q26;p13) in the malignant cells from five patients with acute transformation of myelodysplastic syndrome or blast crisis of chronic myelogenous leukemia. t(3;12)(q26;p13) appears as a rare but nonrandom event present in various myeloid leukemia subtypes, which is frequently associated with dysplasia of megakaryocytes, multilineage involvement, short duration of any blastic phase, and a very poor prognosis. Here, we report the molecular cytogenetic analysis of the t(3;12). Fluorescence in situ hybridization results indicate that the 3q26 breakpoints are quite heterogeneous and occur 5' of MDS1, 3' of EVI1, or between MDS1 and EVI1. Our results are very similar to those observed in other 3q26 rearrangements in which breakpoints were shown to occur over considerable distances 5' and 3' of EVI1. Fluorescence in situ hybridization investigations proved that, in three myelodysplastic syndrome cases with t(3;12)(q26;p13), the 12p 13 breakpoint occurred within the TEL gene.

Adult↗
PubMed1996

Lack of TEL-AML1 fusion transcript resulting from a cryptic t(12;21) in adult B lineage acute lymphoblastic leukemia in Taiwan.

Cryptic t(12;21)(p12-13;q22) leading to TEL-AML1 fusion has recently been recognized as the most frequent genetic rearrangement in childhood acute lymphoblastic leukemia (ALL) in Western countries. More recently, we found a similar frequency of this abnormality in Chinese children with ALL in Taiwan. In this study, we assessed further the frequency of TEL-AML1 fusion as well as that of BCR-ABL in Chinese adults with ALL, using reverse transcriptase-polymerase chain reaction assays. Among the 81 cases with newly diagnosed B lineage ALL studied, none had the TEL-AML1 fusion whereas 30 had the BCR-ABL fusion. The lack of cases with the TEL-AML1 fusion together with the high frequency of BCR-ABL fusion could largely account for the poorer outcome of adult ALL as compared with childhood ALL.

Adolescent↗
PubMed1997

Fusion of ETV6 to MDS1/EVI1 as a result of t(3;12)(q26;p13) in myeloproliferative disorders.

We identified a fusion between ETV6 on 12p13 and MDS1/EVI1 on 3q26 in a t(3;12)(q26;p13) found in two cases of myeloproliferative disorder. The resulting chimeric transcript consists of the first two exons of ETV6 fused to MDS1 sequences, which in turn is fused to the second exon of the EVI1 gene. It has recently been reported that MDS1 can be expressed in normal tissues both as a single gene and fused to EVI1. ETV6 does not contribute any known functional domain to the predicted fusion protein. Association with blast crisis and myelodysplastic syndrome-derived leukemia, bad prognosis, and relative complex karyotype are in agreement with observations made in other cases of t(3;12)(q26;p13). Furthermore, a comparison can be made with the formation of an AML1/MDS1/EVI1 fusion gene in translocations (3;21)(q26;q22).

Adult↗
PubMed1997

BCR/ABL-negative chronic myeloid leukemia with ETV6/ABL fusion.

A BCR/ABL-negative chronic myeloid leukemia (CML) with t(12;14) (p12;q11-13) as the sole chromosomal abnormality was investigated by fluorescence in situ hybridization (FISH), which disclosed a cryptic insertion of ETV6 (previously called TEL), located at 12p12, into ABL at chromosome band 9q34. ETV6/ABL fusion was confirmed by RT-PCR, revealing that the first five exons of ETV6 were fused in frame with ABL at exon 2. Wild-type ETV6 was expressed, in accordance with the FISH results showing no deletion of the second ETV6 allele. ETV6/ABL chimeric transcripts have previously been reported in acute leukemias, but never before in CML. The present case suggests that ETV6/ABL positivity may constitute a new genetic subgroup of BCR-negative CML.

Adult↗
PubMed1997

Heterogeneity in the breakpoints in balanced rearrangements involving band 12p13 in hematologic malignancies identified by fluorescence in situ hybridization: TEL (ETV6 ) is involved in only one half.

Using fluorescence in situ hybridization (FISH) and probes located on 12p12.1 to 13.3, we studied the breakpoints of 23 patients who had various hematologic malignant diseases and who had 12p13-balanced translocations (21 patients), inversion (1 patient), or insertion (1 patient). Among them, 14 patients had breakpoints within YAC964c10, which contains the TEL (ETV6 ) gene and in 12 of these with balanced translocations or insertion, the FISH results suggested that TEL was involved. Two of the 14 patients, patients no. 13 and 14, had breakpoints in YAC 964C10 that were centromeric to TEL but telomeric to KIP1. In the other 9 patients whose breakpoints did not fall within the YAC, the breakpoints were found telomeric to the YAC in at least three different locations on distal 12p. These results indicated that TEL was involved in only half (12 of 23) of the patients with balanced 12p13 rearrangements and that there probably were several other breakpoint cluster regions on 12p13, suggesting that genes other than TEL were involved in these rearrangements.

Adult↗