ETV6

1JI7, 1LKY, 2DAO, 2QAR, 2QB0, 2QB1212014011ENSG00000139083ENSMUSG00000030199P41212P97360NM_001987NM_007961NM_001303102NP_001978NP_001290031NP_031987ETV6 (i.e. translocation-Ets-leukemia virus) protein is a transcription factor that in humans is encoded by the ETV6 (previously known as TEL) gene. The ETV6 protein regulates the development and growth of diverse cell types, particularly those of hematological tissues. However, its gene, ETV6 frequently suffers various mutations that lead to an array of potentially lethal cancers, i.e., ETV6 is a clinically significant proto-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 or tumor suppressor gene in that mutations in it that encode for a truncated and therefore inactive protein are also associated with certain types of cancers.1ji7: Crystal Structure of TEL SAM Polymer1lky: Structure of the wild-type TEL-SAM polymer2dao: Solution structure of ETS domain Transcriptional factor ETV6 protein ETV6 (i.e. translocation-Ets-leukemia virus) protein is a transcription factor that in humans is encoded by the ETV6 (previously known as TEL) gene. The ETV6 protein regulates the development and growth of diverse cell types, particularly those of hematological tissues. However, its gene, ETV6 frequently suffers various mutations that lead to an array of potentially lethal cancers, i.e., ETV6 is a clinically significant proto-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 or tumor 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 human ETV6 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 8 exons and two start 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. Mice depleted of the ETV6 gene by Gene knockout die between day 10.5 and 11.5 of embryonic life with defective yolk sac angiogenesis and extensive losses in mesenchymal and neural cells due to apoptosis. Other genetic manipulation studies in mice indicate that the gene is required for the development and maintenance of bone marrow-based blood cell formation and the vascular network. The human ETV6 protein is a member of the ETS transcription factor family; however, it more often acts to inhibit than stimulate transcription of its target genes. ETV6 protein contains 3 domains: a) the pointed N-terminal (i.e. PNT) domain which forms oligomer 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; and c) the C-terminal DNA-binding domain, ETS, which binds to the consensus DNA sequence, 5-GGAA/T-3 within a 9-to-10 bp sequence, in the target genes it regulates. ETV6 interacts with other proteins that regulate the differentiation and growth of cells. It binds to and thereby inhibits FLI1, another member of the ETS transcription factor family, which is active in promoting the maturation of blood platelet-forming megakaryocytes and blocking the Cellular differentiation of erythroblasts into red blood cells; this results in the excessive proliferation and abnormal morphology of erythroblasts. ETV6 likewise binds to HTATIP, a histone acetyl transferase that regulates the expression of various genes involved in gene transcription, DNA repair, and cellular apoptosis; this binding promotes the transcription-repressing activity of ETV6. Rare missense and other loss of function mutations in ETV6 cause thrombocytopenia 5, an autosomal dominant familial disease characterized by variable thrombocytopenia (blood platelet counts from 5% to 90% of normal), mild to modest bleeding tendencies, and bone marrow biopsy findings of abnormal appearing megakaryocytes (i.e. nuclei with fewer than the normal number of lobulations) and red cell macrocytosis. Thrombocytopenia 5 is associated with an increased incidence of developing hematological (e.g. chronic myelomonocytic leukemia, acute myelocytic leukemia, B cell acute lymphoblastic leukemia, mixed phenotype acute leukemia, Myelodysplastic syndrome, and multiple myeloma) and non-hematological (e.g. skin and colon) cancers as well as non-malignant diseases such as refractory anemia myopathies, and gastroesophageal reflux disease. Two unrelated kindreds were found to have autosomal dominant inherited mutations in the ETV6 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 pairs ETV6 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) and acute 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 with renal cell carcinoma and another family member with Duodenal 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. Family members with thrombocytopenia 5 need to be regularly monitored with complete blood count and blood 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. The acute lymphoblastic leukemia associated with L349P or N385fs mutations in ETV6 appeared far less sensitive to standard chemotherapy for acute lymphoblastic leukemia with 2 among 3 family members moving rather quickly from chemotherapy to bone marrow transplantation and the third family member expiring. This suggest that these mutation-related forms of acute lymphoblastic leukemia require aggressive therapy. The ETV6 gene is prone to develop a wide range of acquired mutations in hematological precursor cells that lead to various types of leukemia and/or lymphoma. It may also suffer a smaller number of mutations in non-hematological tissues that leads to solid tumors. These mutations involve chromosome translocations which fuse the ETV6 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 a fusion gene of the oncogene category which encodes a chimeric 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 with tyrosine 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. 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 in pluripotent hematopoietic stem cells that differentiate into various types of mature hematological cells. Consequently, a given mutation may lead to various types of hematological malignancies. 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 of ETV6 gene mutations in myelodysplastic syndromes is associated with shortened survival.)