Disease relevance of ETV6

• A novel ETV6-NTRK3 gene fusion in congenital fibrosarcoma [1].
• 12p abnormalities and the TEL gene (ETV6) in childhood acute lymphoblastic leukemia [2].
• We conclude that most but not all 12p cytogenetic abnormalities in childhood ALL involve ETV6, and that rearrangement of ETV6 is associated with a favorable treatment outcome [2].
• Evidence for position effects as a variant ETV6-mediated leukemogenic mechanism in myeloid leukemias with a t(4;12)(q11-q12;p13) or t(5;12)(q31;p13) [3].
• 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 [4].

Psychiatry related information on ETV6

• METHOD: The study was conducted at three adolescent psychiatric departments in two mental health centers in the Tel Aviv area [5].
• To summarize our 10-year experience with autistic children at the Tel Aviv Child Development Center, the files of all 55 children with autism treated at our center over a 10-year period were retrospectively reviewed [6].
• Matched population samples from this kibbutz and the city of Tel Aviv revealed significant differences in dietary habits [7].
• The center serves the Tel Aviv area for a variety of developmental disabilities [8].
• A joint intake interview questionnaire and a dental anxiety scale explored the level, background and concomitant factors of dental anxiety among patients at the Universities of Tel Aviv (Israel), Goteborg (Sweden), and Pittsburgh (USA) [9].

High impact information on ETV6

• Moreover, ETV6-NTRK3 gene fusions provide a potential diagnostic marker for CFS [1].
• A t(9;12)(p24;p13) chromosomal translocation in a T cell childhood acute lymphoblastic leukemia patient was characterized and shown to fuse the 3' portion of JAK2 to the 5' region of TEL, a gene encoding a member of the ETS transcription factor family [10].
• Our data pinpoint a critical role for TEL in the normal transition of hematopoietic activity from fetal liver to bone marrow [11].
• The TEL (translocation-Ets-leukemia or ETV6) locus, which encodes an Ets family transcription factor, is frequently rearranged in human leukemias of myeloid or lymphoid origins [11].
• The TEL/ETV6 gene is required specifically for hematopoiesis in the bone marrow [11].

Chemical compound and disease context of ETV6

• The human ABL2 (or ARG) gene codes for a nonreceptor tyrosine kinase is involved in translocation with the ETV6 gene in human leukemia and has an altered expression in several human carcinomas [12].
• We tested four histologically confirmed cases of SBC for the presence of the ETV6-NTRK3 gene fusion and then applied the FISH assay to tissue microarrays (TMAs) in order to screen 481 cases of formalin-fixed, paraffin-embedded invasive breast carcinomas of various histologic subtypes [13].
• Here we describe the clinical and genetic response to imatinib mesylate treatment of an ETV6/ABL1-positive CML patient diagnosed in blast crisis (BC) [14].
• Acute lymphoblastic leukemia with TEL-AML1 fusion has lower expression of genes involved in purine metabolism and lower de novo purine synthesis [15].
• Detection of dual TEL-ABL transcripts and a Tel-Abl protein containing phosphotyrosine in a chronic myeloid leukemia patient [16].

Biological context of ETV6

• Our results also indicate that the transactivation characteristics of ETV6/CBFA2 are a combination of positive and negative regulatory properties [17].
• The ETV6 gene (also known as TEL) is the main target of chromosomal translocations affecting chromosome band 12p13 [18].
• The ETV6 gene (first identified as TEL) is a frequent target of chromosomal translocations in both myeloid and lymphoid leukemias [3].
• Hybridization with cosmid probes showed that the ETV6 gene was rearranged in this translocation [19].
• Our results indicate that, besides the generation of fusion transcripts, deregulation of the expression of oncogenes could be a variant leukemogenic mechanism for translocations involving the 5' end of ETV6, especially for those translocations lacking functionally significant fusion transcripts [3].

Anatomical context of ETV6

• Transplantation of bone marrow cells expressing ETV6-CDX2 failed to induce leukemia [20].
• Breakage and fusion of the TEL (ETV6) gene in immature B lymphocytes induced by apoptogenic signals [21].
• The ETV6/ARG protein may be involved in the unique differentiation capacity of this cell line [22].
• Fusion of ETV6 to fibroblast growth factor receptor 3 in peripheral T-cell lymphoma with a t(4;12)(p16;p13) chromosomal translocation [23].
• To identify ETV6/RUNX1-regulated genes, we used expression profiling and HDACi in lymphoid cells [24].

Associations of ETV6 with chemical compounds

• The tyrosine kinase abl-related gene ARG is fused to ETV6 in an AML-M4Eo patient with a t(1;12)(q25;p13): molecular cloning of both reciprocal transcripts [25].
• STI571 effectively suppressed overall tyrosyl phosphorylation of intracellular proteins including ETV6/ARG fusion protein, as well as the growth of HT93A cells with an IC(50) of 200 nM [26].
• We studied immunohistochemical expression of NTRK3, and conducted a reverse transcription-polymerase chain reaction (RT-PCR) assay to detect the ETV6-NTRK3 fusion transcripts using archival formalin-fixed paraffin-embedded tissues from 10 CIFSs [27].
• We report the transient response of a patient with the ETV6-ABL fusion gene to imatinib mesylate (STI571) [28].
• ETV6-AML1 translocation breakpoints cluster near a purine/pyrimidine repeat region in the ETV6 gene [29].

Physical interactions of ETV6

• Molecular cytogenetic analysis confirmed that formation of an ETV6/ABL1 fusion in these patients required at least three chromosomal breaks and showed that each of these translocations is the result of a complex chromosomal rearrangement [30].
• Our studies show that UBC9 binds to TEL exclusively through the HLH domain of TEL [31].
• We found that H-L(3)MBT binds in vivo to TEL, and we have mapped the region of interaction to their respective SPM/SAM domains [32].
• This is the first report of a complex cytogenetic clone, in association with an ETV6/AML1 fusion, developing in utero [33].
• The ets family member Tel binds to the Fli-1 oncoprotein and inhibits its transcriptional activity [34].

Enzymatic interactions of ETV6

• The second ETV6 allele is not necessarily deleted in acute leukemias with a ETV6/ABL fusion [35].
• Fluorescent in-situ hybridization and loss of heterozygosity studies showed that 73% of the ETV6-CBFA2 samples had a fully or partially deleted second ETV6 allele, explaining the lack of wild-type expression in these patients [36].
• In addition, c-Crk II and CRKL are tyrosine phosphorylated and complexed with numerous other tyrosine phosphorylated proteins in Tel-Abl expressing Ba/F3 cells [37].

Regulatory relationships of ETV6

• It appears that loss of TEL function activates a pathway that cooperates with TEL/RUNX1 and sequesters coactivator(s) into nonfunctional complex in the cytoplasm thus inhibiting transcription of target genes [38].
• Although both proteins are transcriptional inhibitors binding similar DNA recognition sequences, they have opposite biologic effects: TEL inhibits proliferation while TEL2 promotes it [39].
• Confirming these results, overexpression of TEL repressed Stat3 transcriptional activity [40].
• The v-SRC-induced nucleo-cytoplasmic delocalization of TEL-M1 does not involve phosphorylation of the SRCD and does not require TEL self-association and repressive domains [41].
• The rearrangement might also modify the regulation of BAZ2A by either activating a cryptic promoter or by coming under the control of the ETV6 promoter [42].

Other interactions of ETV6

• Analysis of mRNA revealed the expression of ETV6-NTRK3 chimaeric transcripts in all three CFS tumours analysed [1].
• We show here that a t(9;12)(p24;p13) in a case of early pre-B acute lymphoid leukemia and a t(9;15;12)(p24;q15;p13) in atypical chronic myelogenous leukemia in transformation involve the ETV6 gene at 12p13 and the JAK2 gene at 9p24 [43].
• In addition, the putative loss of wild-type function of CDKN1B and ETV6 could indicate a synergistic effect of both genes in the pathogenesis of this leukemia case [44].
• We identified a novel ETV6 partner gene, fibroblast growth factor receptor 3 (FGFR3), in a patient with peripheral T-cell lymphoma (PTCL) with a t(4;12)(p16;p13) translocation [23].
• 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 [45].
• The ETV6-NCOA2 transcript encodes a chimeric protein that consists of the pointed protein interaction motif of ETV6 that is fused to the COOH terminus of NCOA2, including the cyclic AMP-responsive element binding protein-binding protein (CBP) interaction and the AD2 activation domains [46].

Analytical, diagnostic and therapeutic context of ETV6

• The reciprocal transcript ARG-ETV6 was also detected in the patient RNA by reverse transcriptase-polymerase chain reaction (RT-PCR), although at a lower expression level [25].
• Importantly, ETV6 rearrangement was associated with a favorable prognosis (5-year event-free survival: 89% +/- 6% v 60% +/- 1%, P < .01) [2].
• Blast cells were tested for ETV6 and MLL rearrangement using Southern blot analysis [47].
• TEL/ETV6 is a signal transducer and activator of transcription 3 (Stat3)-induced repressor of Stat3 activity [40].
• Furthermore, sequence analysis of the ETV6 PCR product revealed no point mutations which would influence the amino acid sequence [35].

References