ETV6 (i.e. translocation-Ets-leukemia virus) protein is atranscription factor that in humans is encoded by theETV6 (previously known asTEL)gene. The ETV6 protein regulates the development and growth of diverse cell types, particularly those ofhematological tissues. However, its gene,ETV6 frequently suffers various mutations that lead to an array of potentially lethal cancers, i.e.,ETV6 is a clinically significantproto-oncogene in that it can fuse with other genes to drive the development and/or progression of certain cancers. However,ETV6 is also an anti-oncogene ortumor suppressor gene in that mutations in it that encode for a truncated and therefore inactive protein are also associated with certain types of cancers.
The humanETV6 gene is located at position "13.2" on the short (i.e. "p") arm of chromosome 12, i.e. its notated position is 12p13.2. The gene has 8exons and twostart codons, one located at exon 1 at the start of the gene and an alternative located upstream of exon 3.ETV6 codes for a full length protein consisting of 452 amino acids; the gene is expressed in virtually all cell types and tissues.[5][6] Mice depleted of theETV6 gene byGene knockout die between day 10.5 and 11.5 of embryonic life with defectiveyolk sacangiogenesis and extensive losses inmesenchymal andneural cells due toapoptosis. Other genetic manipulation studies in mice indicate that the gene is required for the development and maintenance ofbone marrow-basedblood cell formation and the vascular network.[5][7]
The human ETV6 protein is a member of theETS transcription factor family; however, it more often acts to inhibit than stimulate transcription of its target genes. ETV6 protein contains 3domains:a) the pointed N-terminal (i.e. PNT) domain which formsoligomer partners with itself as well as other transcription factors (e.g.FLI1) and is required for ETV6's transcriptional repressing activity;b) the central regulatory domain; andc) the C-terminalDNA-binding domain, ETS, which binds to theconsensus DNA sequence, 5-GGAA/T-3 within a 9-to-10 bp sequence, in the target genes it regulates.[5][8] ETV6interacts with other proteins that regulate the differentiation and growth of cells. It binds to and thereby inhibitsFLI1, another member of theETS transcription factor family, which is active in promoting the maturation of bloodplatelet-formingmegakaryocytes and blocking theCellular differentiation oferythroblasts intored blood cells; this results in the excessive proliferation and abnormalmorphology of erythroblasts.[9][7] ETV6 likewise binds toHTATIP, ahistone acetyl transferase that regulates the expression of various genes involved in gene transcription,DNA repair, and cellularapoptosis; this binding promotes the transcription-repressing activity of ETV6.[10]
Raremissense and otherloss of function mutations in ETV6 cause thrombocytopenia 5, anautosomal dominant familial disease characterized by variablethrombocytopenia (blood platelet counts from 5% to 90% of normal), mild to modest bleeding tendencies, andbone marrow biopsy findings of abnormal appearing megakaryocytes (i.e. nuclei with fewer than the normal number of lobulations) and red cellmacrocytosis.[7][11] Thrombocytopenia 5 is associated with an increased incidence of developing hematological (e.g.chronic myelomonocytic leukemia,acute myelocytic leukemia, B cellacute lymphoblastic leukemia, mixed phenotype acute leukemia,Myelodysplastic syndrome, andmultiple myeloma) and non-hematological (e.g. skin and colon) cancers as well as non-malignant diseases such as refractoryanemiamyopathies, andgastroesophageal reflux disease.[11][12]
Two unrelated kindreds were found to haveautosomal dominant inherited mutations in theETV6 gene, one family with a germline DNA substitution termed L349P that lead to replacing leucine with proline at amino acid 349 in the DNA binding domain of the ETV6, the second, termed N385fs, in germline DNA caused the lose of five base pairsETV6 and a truncated ETV6 protein. Both mutant proteins failed to enter cell nuclei normally and had a reduced capacity to target genes regulated by the normal ETV6 protein. Afflicted members of these families had low platelet counts (i.e. thrombocytopenia) andacute lymphoblastic leukemia. Fifteen members of the two kindreds had thrombocytopenia, five of whom also had acute lymphoblastic leukemia. The L249P kindred also had one family member withrenal cell carcinoma and another family member withDuodenal cancer. The relationship of these two cancers to the L249P mutation has not been investigated. In all events these two familial thrombocytopenia syndromes appear distinctly different than the thrombocytopenia 5 syndrome.[13]
Family members with thrombocytopenia 5 need to be regularly monitored withcomplete blood count andblood smear screenings to detect the early changes brought on by the malignant transformations of this disease into hematological neoplasms. Patients who developed these transformations have generally been treated similarly to patients who have the same hematological neoplasms but on a non-familial basis. Patients developing non-malignant hematological or non-hematological solid tumor manifestations of thrombocytopenia 5 are also treated like to patients with the same but no-familial disease.[11][12]
The acute lymphoblastic leukemia associated with L349P or N385fs mutations inETV6 appeared far less sensitive to standardchemotherapy for acute lymphoblastic leukemia with 2 among 3 family members moving rather quickly from chemotherapy tobone marrow transplantation and the third family member expiring. This suggest that these mutation-related forms of acute lymphoblastic leukemia require aggressive therapy.[13]
TheETV6 gene is prone to develop a wide range of acquired mutations in hematological precursor cells that lead to various types ofleukemia and/orlymphoma. It may also suffer a smaller number of mutations in non-hematological tissues that leads tosolid tumors. These mutations involvechromosome translocations which fuse theETV6 on chromosome 12's the short (i.e. "p") arm ("q" stands for long arm) at position p13.2 (site notation: 12p12.2) near to a second gene on another chromosome or, more rarely, its own chromosome. This creates afusion gene of theoncogene category which encodes achimeric protein that promotes the malignant growth of its parent cells. It may be unclear which portion of the newly formed oncoprotein contributes to the ensuing malignancy but fusions between ETV6 and proteins withtyrosine kinase activity generally are converted from a protein with tightly regulated tyrosine kinase activity to an uncontrolled and continuously active tyrosine kinase that thereby promotes the malignant transformation of its parent cells.[14]
The following table lists the more frequently occurring genes to which ETV6 fuses, the function of these genes, these genes' chromosomal locations, the notation designating the most common sites of the translocations of these fused genes, and the malignancies resulting from these translocations. These translocation mutations commonly occur inpluripotenthematopoietic stem cells that differentiate into various types of mature hematological cells. Consequently, a given mutation may lead to various types ofhematological malignancies.[5][14] The table includes abbreviations for tyrosine kinase receptor (TK receptor), non-receptor tyrosine kinase (non-receptor TK), homeobox protein type of transcription factor (homeobox protein), acute lymphocytic leukemia (ALL), Philadelphia chromosome negative chronic myelogenous leukemia (Ph(-)CML), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), and acute myeloid leukemia (AML). The presence ofETV6 gene mutations in myelodysplastic syndromes is associated with shortened survival.[15]
| Gene | function | location | notation | malignancies | gene | function | location | notation | malignancies | |
|---|---|---|---|---|---|---|---|---|---|---|
| PDGFRA | TK receptor | 4q12 | t(4;12)(q27?3;p13) | 40% to 50% ofclonal eosinophilia patients | PDGFRB | TK receptor | 5q32 | t(5;12)(q31-33;p13) | rareclonal eosinophilia patients | |
| FLT3 | TK receptor | 13q12.2 | t(12;13)(q13.1;p12.3-13) | rareAML,ALL, andclonal eosinophilia patients | ABL1 | non-receptor TK | 9q34.12 | t(9;12)(q34;p13) | rareAML, B-cell or T-cellALL, Ph(-)CML patients | |
| RUNX1 | transcription factor | 21q22.12 | t(12;21)(p13;q22) | 20-25% of pediatricALL patients | PAX5 | homeobox protein | 9p13.2 | t(9;12)(q11;p13) | 1% of pediatricALL patients | |
| MNX1 | homeobox protein | 7q36.3 | t(7:12)(q36;p13) | 20-30% of pediatricALL patients less than 18 months old | MECOM | Transcription factor | 3q26.2 | t(3;12)(q26;p13) | rareMDS,MPN, andAML patients |
In addition to the fusion gene-producing translocations given in the table,ETV6 has been reported to fuse with other genes in very rare cases (i.e. 1-10 published reports). These translocations lead to one or more of the same types of hematological malignancies listed in the table. Thus, theETV6 gene reportedly forms translocation-induced fusion genes with:[5]a) tyrosine kinase receptor geneFGFR3;b) non-receptor tyrosine kinase genesABL2,NTRK3,JAK2,SYK,FRK, andLYN;c) transcription factor genesMN1 andPER1;d) homeobox protein transcription factorCDX2;e) Protein tyrosine phosphatase receptor-type R genePTPRR;[16]f) transcriptional coactivator for nuclear hormone receptors geneNCOA2;f)Immunoglobulin heavy chain gene IGH;[17]g) enzyme genesTTL (adds and removes tyrosine residues onα-tubulin),[18]GOT1 (anAspartate transaminase), andACSL6 (aLong-chain-fatty-acid—CoA ligase);h) transporter geneARNT (binds toligand-boundaryl hydrocarbon receptor to aid in its movement to the nucleus where it promotes the expression of genes involved in xenobiotic metabolism);i) unknown function genesCHIC2,[19]MDS2,[20]FCHO2[21] andBAZ2A.;[22] andj) non-annotated geneSTL (which has no longopen reading frame[23]).
At least 9frameshift mutations in the'ETV6 gene have been associated with ~12% of adult T cellAcute lymphoblastic leukemia cases. These mutations involve insertions or deletions in the gene that lead to its encoding a truncated and therefore inactive ETV6 protein. These mutations commonly occur alongside mutations in another oncogene,NOTCH1, which is associated with T cell acute lymphoblastic lymphoma quite independently of ETV6. It is suggested that suppressor mutations in theETV6 gene may be a contributing factor in the development ant/or progression of this leukemia type.[8][24][25]
Patients developing hematological malignancies secondary to theETV6 gene fusion to receptor tyrosine kinases and non-receptor tyrosine kinases may be sensitive to therapy withtyrosine kinase inhibitors.[26] For example, patients with clonal eosinophilias due toPDGFRA orPDGFRB fusion genes experience long-term, complete remission when treated with are highly sensitive tyrosine kinase inhibitor,gleevec.[14]Larotrectinib,entrectinib,merestinib, and server other broadly acting tyrosine kinase inhibitors target theNTRK3 gene. Many of these drugs are in phase 1 or phase 2clinical trials for the treatment ofETV6-NTRK3-related solid tumors and may ultimately prove useful for treating hematologic malignancies associated with this fusion gene.[27] Clinical trials have found that the first generation tyrosine kinase inhibitorssorafenib,sunitinib,midostaurin,lestaurtinib have shown some promise in treatingacute myelogenous leukemia associated with theFLT3-TKI fusion gene; the second generation tyrosine kinase inhibitorsquizartinib andcrenolanib which are highly selective in inhibiting the FLT3 protein, have shown significant promise in treating relapsed and refractory acute myelogenous leukemia related to theFLT3-TKI fusion gene.[28] One patient withETV6-FLT3-related myeloid/lymphoid neoplasm obtained a short term remission on sunitinib and following relapse, on sorafenib suggesting that the cited FLT3 protein tyrosine kinase inhibitors may prove useful for treatingETV6-FLT-related hematologic malignancies.[29] Two patients suffering hematologic malignancies related toPCM1-JAK2 orBCR-JAK2 fusion genes experienced complete and cytogenetic remissions in response to the tyrosine kinase inhibitorruxolitinib; while both remissions were short-term (12 months), these results suggest that tyrosine kinase inhibitors that target JAK2 may be of some use for treating hematologic malignancies associated withETV6-JAK2 fusion stems.[14] An inhibitor of SYK tyrosine kinase, TAK-659 is currently undergoing Phase I clinical trials for advanced lymphoma malignancies and may prove to be useful in treating this disease when associated with theETV6-SYK fusion gene.[30] It is possible that hematological malignancies associated withETV6 gene fusions to either theSYK orFRK tyrosine kinase genes may someday be shown susceptible to tyrosine kinase inhibitor therapy. However, children withETV6-RUNX1-associatedacute lymphoblastic leukemia are in an especially good-risk subgroup and therefore have been almost uniformly treated with standard-riskchemotherapy protocols.[31]
Hematological malignancies associated withETY6 gene fusions to other transcription factor genes appear to reflect a loss or gain in function ofETV6 and/or the other genes in regulating expression of their target genes; this results in the formation or lack of formation of products which influence cell growth, proliferation, and/or survival. In vitro studies ofETV6-RUNX, ETV6-MN1, ETV6-PER1, andETV6-MECOM fusion genes support this notion. Thus, theETV6-MECOM fusion gene is overexpressed because it is driven by thepromoter derived fromETV6[5] whereas theETV6-RUNX, ETV6-MN1, and ETV6-PER1 fusion genes produce chimeric proteins which lack ETV6 protein's gene-suppressing activity.[32] The chimeric protein products ofETV6 gene fusions withARNT, TTL, BA22A, FCHO2, MDS2, andCHIC2 likewise lack ETV6 protein's transcription factor activity.[32] Gene fusions betweenETV6 and the homeobox gens (i.e.CDX2, PAX5, and MNX1) produce chimeric proteins with lack either ETV6s and/or CDX2s, PAX5s or MNX1s transcription factor activity.[5] In all events, hematological malignancies associated with these fusion genes have been treated with standard chemotherapy protocols selected on the basis of the malignanciesphenotype.
Mutations in theETV6 gene are also associated withsolid tumors. In particular, theETV6-NTRK3 fusion gene occurs in and is thought or proposed to drive certain types of cancers. These cancers includesecretory breast cancer (also termed juvenile breast cancer),mammary analogue secretory carcinoma of theparotid and othersalivary glands,congenital fibrosarcoma,congenital mesoblastic nephroma,inflammatory myofibroblastic tumor, and radiation-inducedpapillary thyroid carcinoma.[8][33][34][35][27][36][32][37]
The treatment ofETV6 gene-associated solid tumors has not advanced as far as that forETV6 gene-associated hematological malignancies. It is proposed thattyrosine kinase inhibitors with specificity for NTRK3's tyrosine kinase activity inETV6-NTRK3 gene-associated solid tumors may be of therapeutic usefulness.Entrectinib, a pan-NTRK as well as anALK andROS1 tyrosine kinase inhibitor has been found useful in treating a single patient withETV6-NRTK3 fusion gene-associatedmammary analogue secretory carcinoma and lends support to the clinical development of NTRK3-directed tyrosine kinase inhibitors to treat ETV6-NTRK3 fusion protein associated malignancies.[27] Three clinical trials are in the recruitment phase for determining the efficacy of treating a wide range of solid tumors associated with mutated, overactive tyrosine kinase proteins, including the ETV6-TRK3 protein, withlarotrectinib, a non-selective inhibitor of NTRK1, NTRK2, and NTRK3 tyrosine kinases.[38]
This article incorporates text from theUnited States National Library of Medicine, which is in thepublic domain.
