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Results for “ETS Translocation Variant 6 Protein”

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PubMed1997

Incidence of TEL/AML1 fusion gene analyzed consecutively in children with acute lymphoblastic leukemia in relapse.

The translocation t(12; 21)(p13; q22) is difficult to detect by classic cytogenetics. However, using fluorescence in situ hybridization (FISH) and by screening for the TEL/AML1 rearrangement by the polymerase chain reaction (PCR), it has been demonstrated to be the most frequent known structural chromosomal abnormality in childhood acute lymphoblastic leukemia (ALL). It is closely correlated with a B-cell precursor (BCP) phenotype and is considered a favorable prognostic factor. However, little is known about the incidence of the translocation in relapsed patients and the duration of complete remission (CR) in children expressing the TEL/AML1 fusion gene. We therefore examined 49 bone marrow samples from children with ALL at first or second relapse that were consecutively mailed to our laboratory to test for the presence of t(12; 21) using reverse transcriptase (RT)-PCR. The TEL/AML1 rearrangement could be identified in nine of 44 (20%) of the patients, a result similar to the reported incidence at diagnosis. Most of the TEL/AML1-positive children showed no adverse clinical features at diagnosis (eg, white blood cell [WBC] count <100 x 10(9)/L or age <10 years), and regarding these data, there were no differences versus children who were negative for the fusion gene. However, the period of remission was about 1 year longer in children expressing TEL/AML1 (P = .046), and the majority of relapses in this group appeared late (<2 years after diagnosis). Our findings therefore reinforce the urgent need for further prospective studies with a long follow-up period to determine the true prognostic significance of t(12; 21) and to avoid premature changes of treatment strategies.

Adolescent↗
PubMed1997

Characterization of a t(10;12)(q24;p13) in a case of CML in transformation.

We have used Southern blotting and fluorescence in situ hybridization (FISH) to define the breakpoints of a reciprocal translocation, t(10;12)(q24;p13), acquired as a secondary abnormality in a patient with Philadelphia chromosome positive chronic myeloid leukemia (CML) in transformation. A YAC clone that spanned the breakpoint at 12p13 was identified; this YAC included the CDKN1B gene but did not include ETV6. Neither ETV6 nor CDKN1B was rearranged, as determined by FISH and Southern blotting; however, a small deletion encompassing the translocated CDKN1B allele was detected. Analysis of two candidate genes at 10q24, HOX11 and NFKB2 suggested that they are not involved in this translocation. The preliminary mapping of breakpoints in this case demonstrated that they are different from an apparently identical translocation identified previously in a patient with myelodysplastic syndrome. The identification of the split YAC and small deletion should enable a more focused search for a gene or genes that may contribute to progression from chronic phase to blast crisis in CML.

Blotting, Southern↗
PubMed1998

Translocations involving chromosome 12p11-13, methotrexate metabolism, and outcome in childhood B-progenitor cell acute lymphoblastic leukemia: a Pediatric Oncology Group study.

Children with B-progenitor cell acute lymphoblastic leukemia whose lymphoblasts at diagnosis accumulate high levels of methotrexate (MTX) and MTX polyglutamates (MTXPGs) appear to have a good prognosis. This has been attributed to increased sensitivity of their blast cells to MTX. However, the proportion of children who are cured of B-progenitor cell acute lymphoblastic leukemia exceeds the number whose lymphoblasts accumulate high MTXPG levels. We report that lymphoblasts from patients with < 50 chromosomes who have translocations that involve the short arm of chromosome 12 accumulate low levels of MTXPGs. These patients appear to have an excellent survival because none of 14 patients with translocations affecting 12p has relapsed, 26-79 months following diagnosis.

Antimetabolites, Antineoplastic↗
PubMed1998

Identification of new partner chromosomes involved in fusions with the ETV6 (TEL) gene in hematologic malignancies.

Several partner genes on different chromosomes have been reported to be fused with the ETV6 gene (located in chromosome band 12p13), with different breakpoints and different frequencies, in various hematologic malignancies, particularly acute myeloid and lymphoid leukemias and myelodysplastic syndromes. By using FISH and molecular analyses, we have analyzed five different pediatric and adult patients carrying cytogenetic abnormalities involving 12p13. Our findings demonstrate that ETV6 was rearranged in all the cases analyzed. In particular, ETV6 was disrupted by translocations with chromosomal bands 7q22, 7q36, 9q11, and 13q12, not previously described as partners of ETV6 in translocations, thus extending its promiscuity in rearranging with different partner genes.

Adult↗
PubMed1998

ETV6-NTRK3 gene fusions and trisomy 11 establish a histogenetic link between mesoblastic nephroma and congenital fibrosarcoma.

Congenital mesoblastic nephroma (CMN) is an infantile spindle cell tumor of the kidney that is subdivided into "classical" and "cellular" forms based on the degree of cellularity and mitotic activity. The histogenesis of CMN remains obscure, but relationships to other pediatric renal neoplasms have been proposed. However, cellular CMN is virtually identical histologically to congenital fibrosarcoma (CFS), a malignant tumor of fibroblasts in children of the same age group. Moreover, cytogenetic studies have reported common trisomies in CFS and cellular CMN, particularly of chromosome 11. We show here that t(12;15)(p13;q25)-associated ETV6-NTRK3 gene fusions described in CFS are also present in cellular CMN. ETV6-NTRK3 chimeric transcripts were detected in 8 of 9 cellular CMNs and 2 of 2 mixed CMNs. In contrast, all of the four classical CMNs tested were negative, as were cases of Wilms' tumor and clear cell sarcoma of the kidney. Moreover, we found trisomy 11 only in cellular or mixed CMNs with the ETV6-NTRK3 gene fusion. Our studies indicate that classical and cellular CMN have different genetic features and support the concept that cellular CMN is histogenetically related to CFS. They also provide insight into potential mechanisms involved in the transformation of the classical into the cellular form of CMN.

Child, Preschool↗
PubMed1999

ETV6-AML1 translocation breakpoints cluster near a purine/pyrimidine repeat region in the ETV6 gene.

The t(12;21)(p13;q22) translocation, fusing the ETV6 and AML1 genes, is the most frequent chromosomal translocation associated with pediatric B-cell precursor acute lymphoblastic leukemia. Although the genomic organization of the ETV6 gene and a breakpoint cluster region (bcr) in ETV6 intron 5 has been described, mapping of AML1 breakpoints has been hampered because of the large, hitherto unknown size of AML1 intron 1. Here, we report the mapping of the AML1 gene between exons 1 and 3, cloning of ETV6-AML1 breakpoints from different patients, and localization of the AML1 breakpoints within AML1 intron 1. In contrast to the tightly clustered ETV6 breakpoints, the AML1 breakpoints were found to be dispersed throughout AML1 intron 1. Although nucleotide sequence analysis of the breakpoint junctions showed several 5/7 matches for the V(D)J consensus heptamer recognition sequence, these matches were present only on the ETV6 alleles and not on the AML1 alleles, making it unlikely that the translocations were mediated by a simple V(D)J recombination mistake. Interestingly, several breakpoints as well as a stable insertion polymorphism mapped close to a polymorphic, alternating purine-pyrimidine tract in the ETV6 gene, suggesting that this region may be prone to DNA recombination events such as insertions or translocations. Finally, the presence of an insertional polymorphism within the ETV6 bcr must be recognized to avoid incorrect genotype designation based on Southern blot analysis.

Base Sequence↗
PubMed1999

Fusion of ETV6 to neurotrophin-3 receptor TRKC in acute myeloid leukemia with t(12;15)(p13;q25).

Chromosome translocations involving band 12p13 are known to be involved in a variety of hematologic malignancies, some of them resulting in rearrangement of the ETV6/TEL gene. Applying the fluorescence in situ hybridization (FISH) method, we found a cryptic translocation t(12;15)(p13;q25) in an adult acute myeloid leukemia (AML) patient. Hybridization with cosmid probes showed that the ETV6 gene was rearranged in this translocation. A patient-specific cDNA library was screened with ETV6 cDNA, and a novel fusion transcript was identified between the ETV6 and TRKC/NTRK3 gene located on 15q25. TRKC is a receptor tyrosine kinase that is activated by neurotrophin-3 (NT-3). It is known to be expressed broadly in neural tissues but not in hematologic cells, so far. ETV6-TRKC chimeric transcript encoded the pointed (PNT) domain of the ETV6 gene that fused to the protein-tyrosine kinase (PTK) domain of the TRKC gene. Two types of fusion transcript were determined, one that included the entire PTK domain of TRKC and the other in which the 3'-terminal 462 bp of TRKC was truncated within the PTK domain. Western blot analysis showed the expression of both chimeric proteins of 52 and 38 kD in size. Our results suggest that chimeric PTK expressed in the leukemic cells may contribute to cellular transformation by abnormally activating TRK signaling pathways. Moreover, this is the first report on truncated neurotrophin receptors associated in leukemia.

Acute Disease↗
PubMed1996

Genomic organization of TEL: the human ETS-variant gene 6.

We have constructed a detailed map of the genomic region containing the ETS-variant gene 6 (ETV6), involved in translocations and deletions associated with hematologic malignancies. Thirty-eight cosmids were characterized belonging to two contigs spanning 340 kb, and an EcoRl restriction map was developed. The gap between the two contigs, 2 kb in size, was closed by PCR. The contigs contain the complete coding sequence and the 5' and 3' UTRs of ETV6. Eight exons accounting for the ETV6 cDNA sequence were identified. The helix-loop-helix (HLH) motif is coded by exons 3 and 4, whereas exons 6-8 code for the ETS DNA-binding domain. All introns show consensus 5' donor and 3' acceptor splice sites. Introns 1 and 2 span 100 and 82 kb, respectively, and introns 3-7 range from 15 to 1.3 kb. An alternative exon 1 (exon 1B) is localized in intron 2. The 5' end of the ETV6 gene is associated with a CpG island characterized by the presence of four Notl, four Sacll, and three BssHll recognition sites and several SP1- and AP2-binding motifs. Alternative polyadenylation at the 3' end of the ETV6 gene generates the three transcripts of 6200, 4300, and 2400 nucleotides, respectively. The ETV6 gene spans 240 kb and is flanked at its 5' and 3' end by D12S1697 and D12S98, respectively. The markers D12S1095 and D12S89 are located in the first intron. Two new DNA polymorphisms were identified in the ETV6 gene, which will be useful for the analysis of loss of heterozygosity reported for the ETV6 gene in leukemia.

Base Sequence↗
PubMed2003

Non-resectable congenital tumors with the ETV6-NTRK3 gene fusion are highly responsive to chemotherapy.

BACKGROUND: Recently, the ETV6-NTRK3 gene fusion has been identified in both infantile fibrosarcoma and cellular mesoblastic nephroma. For both these tumors standard curative treatment has been primarily surgical with wide local excision. This has frequently involved radical and even mutilating surgery. PROCEDURE: This report discusses three infants with congenital tumors, two congenital fibrosarcomas, and one atypical congenital mesoblastic nephroma, not easily amenable to surgical intervention. RESULTS: All three were treated with pre-operative chemotherapy with excellent responses negating the need for amputation in two patients. In each patient, the ETV6-NTRK3 gene fusion was identified by reverse transcriptase-polymerase chain reaction (RT-PCR) in the tumor specimens. CONCLUSIONS: Our findings suggest that the ETV6-NTRK3 gene fusion may underlie the distinctive biological properties of these tumors and may also indicate tumor chemosensitivity. In this group of patients pre-operative chemotherapy may abrogate the need for morbid surgical procedures.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2005

Concomitant Ewing sarcoma and acute lymphoblastic leukemia in a 5-year-old girl.

Malignancies from the Ewing family of tumors and acute lymphoblastic leukemia (ALL) are not known to be associated with each other. A 5-year-old girl was incidentally found to suffer from acute lymphoblastic leukemia during bone marrow staging for Ewing sarcoma of the radius. The simultaneous presence of two distinct neoplasms was confirmed by RT-PCR, with EWS/FLI1 type 1 rearrangement in the bone tumor and TEL/AML1 rearrangement in the marrow. She was treated with chemotherapy, radiotherapy, and surgery and was in remission of both diseases 31 months after diagnosis.

Child, Preschool↗
PubMed2004

ABL-fusion oncoproteins activate multi-pathway of DNA repair: role in drug resistance?

Chromosomal translocations of tyrosine kinase c-ABL gene from chromosome 9 may generate oncogenic kinases exhibiting constitutive tyrosine kinase activity. Recently, we have shown that ABL-fusion oncogenic tyrosine kinases, BCR/ABL and TEL/ABL, specific to hematopoietic malignances, induced resistance to DNA-damaging agents. To elucidate the role of DNA repair in this phenomenon we examined the capacity of murine BaF3 lymphoid cells and their TEL/ABL-transformed counterparts to repair DNA lesions caused by gamma- and UV-radiations and the anti-cancer drug, idarubicin. TEL/ABL-transformed cells displayed resistance to these DNA damaging agents as evaluated by MTT assay and the survival advantage was associated with an accelerated kinetics of DNA repair as measured by the alkaline comet assay. Deoxyribonucleosides (dNTPs) supplementation of the repair medium further stimulated DNA repair and the effect was specific to the DNA damage agent used in the experiment but only the transformed cells displayed this feature. A variety of damages induced imply the multi-pathway of DNA repair involved. We also examined the capability of BCR/ABL-fusion to modulate the repair of oxidative lesions, considered as a major side effect of various anti-cancer drugs including idarubicin and radiation. Employing the free radical scavenger alpha-phenyl-N-tert-butyl nitrone (PBN, a spin trap) and DNA repair enzymes: endonuclease III (EndoIII) that nicks DNA at sites of oxidized bases, we found that BCR/ABL-transformed cells repaired oxidative DNA lesions more effectively than control cells. Our results suggest, that oncogenic ABL-dependent stimulation of DNA repair may contribute to the cell resistance to genotoxic treatment.

Animals↗
PubMed2002

Fluorescence in situ hybridization analysis of the cryptic t(12;21) (p13;q22) in childhood B-lineage acute lymphoblastic leukemia.

We evaluated retrospectively the cryptic t(12;21)(p13;q22) in 15 children with early B-lineage acute lymphocytic leukemia who had a normal karyotype by using the locus specific probes of TEL and AML1 genes in a dual color fluorescence in situ hybridization (FISH). The FISH analysis revealed six patients with the fusion gene TEL/AML1 on chromosome 21, three of whom possessed a double fusion gene. In addition, the AML1 probe revealed hyperdiploid clones that were not detected in the conventional cytogenetic analysis. A discrepancy between the proportion of cells with the fusion gene in interphase nuclei and metaphases was noted.

Burkitt Lymphoma↗
PubMed1997

Two unbalanced translocations, t(12;22)(p13;q11) and t(12;?)(p13;?), in an aggressive chronic B-cell leukemia: TEL gene analysis using FISH.

The translocation t(12;22)(p13;q11) has been consistently described in myeloid malignancies and shown to result from a fusion between the TEL and MN1 genes. Previously described deletions of 12p in acute lymphoblastic leukemias have been recently shown to harbor undetected translocations involving the TEL gene at 12p13. We document a case of an aggressive chronic B-cell leukemia whose cells had trisomy 12 and two unbalanced translocations involving 12p13, including a t(12;22)(p13;q11) as shown by conventional cytogenetics and fluorescence in situ hybridization (FISH). The 12p13 breakpoint of the t(12;22)(p13;q11) was telomeric to the TEL gene, and the second unbalanced translocation with breakpoint 12p13 resulted in the deletion of TEL. This case demonstrates that TEL gene deletions may be relevant in cases of mature B-lymphoproliferative diseases.

Chromosomes, Human, Pair 12↗
PubMed2002

ETV6-NTRK3--Trk-ing the primary event in human secretory breast cancer.

In this issue of Cancer Cell, propose a single chromosomal translocation as the cause of a particularly troubling form of breast cancer, secretory carcinoma. They challenge widely held beliefs concerning breast carcinogenesis as well as beliefs concerning the absolute association of specific fusion genes with specific tumor types. Their data highlight the role of Trk signaling in breast cancer and also suggest a target for drug development.

Artificial Gene Fusion↗
PubMed1997

The common TEL/AML1 rearrangement does not represent a frequent event in acute lymphoblastic leukaemia occuring in children with Down syndrome.

Individuals with constitutional trisomy 21 (Down syndrome) are at increased risk of developing acute leukaemias, both of myeloid and lymphoid lineage. Although the cause of leukaemia in Down syndrome (DS) remains unknown, potential candidate genes include the ones on chromosome 21, and in particular AML1, the rearrangement of which in the t(8,21) is associated with the French-American-British (FAB) classification M2 subtype of acute myeloid leukaemia (AML) in the general population and has been described in Down patients with AML-M2. Recently, a new rearrangement involving AML1, the t(12;21), producing the TEL/AML1 hybrid transcript, has been described by molecular analysis as the most recurrent genetic lesion in childhood acute lymphoblastic leukemia (ALL). In order to investigate whether the t(12;21) could give a molecular clue as to the precise basis of the etiologic association between DS and acute lymphoblastic leukemia, we tested a series of 11 consecutive cases of ALL in DS children for the presence of the TEL/AML1 transcript, by RT-PCR analysis. We report absence of the TEL/AML1 rearrangement among the 11 cases tested. This data may be suggestive of alternative pathways involved in the pathogenesis of ALL in children with constitutional trisomy 21.

Adolescent↗