# ETV6

## Overview
ETV6, also known as TEL, is a gene that encodes the ETS variant transcription factor 6, a member of the ETS family of transcription factors. This protein functions primarily as a transcriptional repressor and is characterized by its pointed (PNT) domain and ETS DNA-binding domain, which facilitate protein-protein interactions and DNA binding, respectively (Green2010DNA; De2014Steric). ETV6 plays a crucial role in hematopoiesis, the process of blood cell formation, and is essential for the development and maintenance of hematopoietic stem cells (HSCs) (Wang1998The). The protein's ability to form homodimers and heterodimers, along with its interactions with various corepressors, underscores its importance in regulating gene expression (Putnik2007The; Gerak2021Biophysical). Mutations in the ETV6 gene are associated with several hematological malignancies and conditions, including thrombocytopenia and leukemia, highlighting its clinical significance in both hematopoietic disorders and oncogenesis (Feurstein2017Germline; Di2019ETV6-related).

## Structure
ETV6, also known as TEL, is a transcriptional repressor that contains two primary domains: the pointed (PNT) domain and the ETS DNA-binding domain. The PNT domain facilitates protein-protein interactions and is capable of forming stable polymers through head-to-tail self-association, which may influence the DNA-binding properties of the full-length protein (Green2010DNA). The ETS domain is responsible for binding to DNA, specifically recognizing the ETS consensus motif 5′ GGAA 3′. This domain adopts a winged helix-turn-helix fold typical of ETS family proteins (De2014Steric).

The ETV6 protein undergoes autoinhibition through its C-terminal inhibitory domain (CID), which consists of two α-helices. One of these helices blocks the DNA-binding surface of the ETS domain, reducing DNA-binding affinity by approximately 10-fold (Green2010DNA). The inhibitory helix H5 is crucial for this autoinhibition, as it undergoes a folded-to-unfolded transition to allow DNA binding (De2014Steric).

ETV6 can form both homodimers and heterodimers, which influence its function. The protein's structure is further stabilized by specific salt bridges and hydrogen bonds, contributing to its rigidity and stability in both monomeric and heterodimeric forms (Gerak2021Biophysical).

## Function
ETV6, also known as TEL, is a transcription factor that plays a critical role in hematopoiesis, the process of blood cell formation, particularly within the bone marrow. It is essential for the development and maintenance of hematopoietic stem cells (HSCs) and multipotential progenitor cells in the bone marrow, ensuring the stable colonization and survival of these cells in the bone marrow microenvironment (Wang1998The). ETV6 is involved in the regulation of adhesive interactions between hematopoietic cells and the bone marrow stroma, which are crucial for the migration, retention, and proliferation of HSCs (Wang1998The).

ETV6 functions as a transcriptional repressor, primarily through its helix-loop-helix (HLH) and ETS domains, interacting with corepressors that recruit histone deacetylases to modulate gene expression (De2014ETV6). It is ubiquitously expressed, with higher levels in the bone marrow, spleen, and thymus, and is localized in the nucleus where it binds specific DNA sequences through its ETS domain (De2014ETV6; Montpetit2001Comparative). ETV6's role extends to embryonic development, where it is crucial for maintaining blood vessel integrity and the survival of various cell types (De2014ETV6).

## Clinical Significance
Mutations in the ETV6 gene are associated with a range of hematological malignancies and conditions. Germline mutations in ETV6 are linked to autosomal dominant thrombocytopenia, characterized by decreased platelet numbers and a tendency to bleed, often presenting in childhood (Feurstein2017Germline). These mutations also predispose individuals to acute lymphoblastic leukemia (ALL), myelodysplastic syndrome (MDS), and acute myeloid leukemia (AML) (Feurstein2017Germline; Hock2017ETV6). ETV6 mutations are frequently involved in chromosomal translocations, such as the ETV6-RUNX1 fusion, which occurs in 22% of children with B-cell ALL (Di2019ETV6-related).

ETV6 mutations can lead to impaired megakaryocyte maturation, contributing to thrombocytopenia (Melazzini2016Clinical). The mutations often occur in the ETS domain, responsible for DNA binding, and can result in decreased transcriptional repression and altered cellular localization (Noetzli2015Germline). In addition to hematological malignancies, ETV6 gene aberrations are implicated in non-hematological cancers through fusion genes, such as ETV6-NTRK3, associated with secretory breast cancer and other solid tumors (Biswas2020ETV6). These genetic alterations highlight ETV6's significant role in both hematopoietic disorders and broader oncogenic processes.

## Interactions
ETV6, also known as TEL, is a transcription factor that participates in various protein-protein interactions, playing a significant role in hematopoiesis and oncogenesis. ETV6 interacts with the HIV Tat interacting protein (TIP60), a histone acetyltransferase, through a functional acetyltransferase domain in TIP60. This interaction acts as a corepressor of ETV6, influencing its transcriptional activity (Putnik2007The). ETV6 also interacts with other MYST domain histone acetyltransferases like MOZ and MORF, suggesting a conserved mechanism of interaction (Putnik2007The).

ETV6 forms complexes with the human l(3)mbt polycomb group protein (H-L(3)MBT) through their SPM/SAM domains, indicating a role in transcriptional repression (Boccuni2003The). It can dimerize with the ets-family transcription factor FLI1, inhibiting its transcriptional activity (Putnik2007The; Kwiatkowski1998The). ETV6 also interacts with nuclear corepressors such as mSin3a, N-CoR, and SMRT, which are involved in its function as a transcriptional repressor (Putnik2007The).

Mutations in ETV6 can lead to mislocalization of the protein and its associated repressor complex, HDAC3/NCOR2, resulting in transcriptional dysregulation (Fisher2020ETV6). These interactions highlight ETV6's critical role in regulating gene expression and maintaining normal cellular functions.


## References


[1. (Feurstein2017Germline) Simone Feurstein and Lucy A. Godley. Germline etv6 mutations and predisposition to hematological malignancies. International Journal of Hematology, 106(2):189–195, May 2017. URL: http://dx.doi.org/10.1007/s12185-017-2259-4, doi:10.1007/s12185-017-2259-4. This article has 64 citations and is from a peer-reviewed journal.](https://doi.org/10.1007/s12185-017-2259-4)

[2. (Green2010DNA) Sean M. Green, H. Jerome Coyne, Lawrence P. McIntosh, and Barbara J. Graves. Dna binding by the ets protein tel (etv6) is regulated by autoinhibition and self-association. Journal of Biological Chemistry, 285(24):18496–18504, June 2010. URL: http://dx.doi.org/10.1074/jbc.m109.096958, doi:10.1074/jbc.m109.096958. This article has 96 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/jbc.m109.096958)

[3. (Fisher2020ETV6) Marlie H. Fisher, Gregory D. Kirkpatrick, Brett Stevens, Courtney Jones, Michael Callaghan, Madhvi Rajpurkar, Joy Fulbright, Megan A. Cooper, Jesse Rowley, Christopher C. Porter, Arthur Gutierrez-Hartmann, Kenneth Jones, Craig Jordan, Eric M. Pietras, and Jorge Di Paola. Etv6 germline mutations cause hdac3/ncor2 mislocalization and upregulation of interferon response genes. JCI Insight, September 2020. URL: http://dx.doi.org/10.1172/jci.insight.140332, doi:10.1172/jci.insight.140332. This article has 20 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1172/jci.insight.140332)

[4. (Kwiatkowski1998The) Boguslaw A. Kwiatkowski, L. Scot Bastian, Thomas R. Bauer, Schickwann Tsai, Anna G. Zielinska-Kwiatkowska, and Dennis D. Hickstein. The ets family member tel binds to the fli-1 oncoprotein and inhibits its transcriptional activity. Journal of Biological Chemistry, 273(28):17525–17530, July 1998. URL: http://dx.doi.org/10.1074/jbc.273.28.17525, doi:10.1074/jbc.273.28.17525. This article has 107 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/jbc.273.28.17525)

[5. (Putnik2007The) Jasmina Putnik, Chang-Dong Zhang, Leticia Fröhlich Archangelo, Belay Tizazu, Sigrun Bartels, Michael Kickstein, Philipp A. Greif, and Stefan K. Bohlander. The interaction of etv6 (tel) and tip60 requires a functional histone acetyltransferase domain in tip60. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1772(11–12):1211–1224, December 2007. URL: http://dx.doi.org/10.1016/j.bbadis.2007.09.006, doi:10.1016/j.bbadis.2007.09.006. This article has 12 citations.](https://doi.org/10.1016/j.bbadis.2007.09.006)

[6. (Wang1998The) Li Chun Wang, Wojciech Swat, Yuko Fujiwara, Laurie Davidson, Jane Visvader, Frank Kuo, Fred W. Alt, D. Gary Gilliland, Todd R. Golub, and Stuart H. Orkin. The tel/etv6 gene is required specifically for hematopoiesis in the bone marrow. Genes & Development, 12(15):2392–2402, August 1998. URL: http://dx.doi.org/10.1101/gad.12.15.2392, doi:10.1101/gad.12.15.2392. This article has 212 citations.](https://doi.org/10.1101/gad.12.15.2392)

[7. (Di2019ETV6-related) Jorge Di Paola and Christopher C. Porter. Etv6-related thrombocytopenia and leukemia predisposition. Blood, 134(8):663–667, August 2019. URL: http://dx.doi.org/10.1182/blood.2019852418, doi:10.1182/blood.2019852418. This article has 0 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1182/blood.2019852418)

[8. (Melazzini2016Clinical) Federica Melazzini, Flavia Palombo, Alessandra Balduini, Daniela De Rocco, Caterina Marconi, Patrizia Noris, Chiara Gnan, Tommaso Pippucci, Valeria Bozzi, Michela Faleschini, Serena Barozzi, Michael Doubek, Christian A. Di Buduo, Katerina Stano Kozubik, Lenka Radova, Giuseppe Loffredo, Sarka Pospisilova, Caterina Alfano, Marco Seri, Carlo L. Balduini, Alessandro Pecci, and Anna Savoia. Clinical and pathogenic features of etv6 -related thrombocytopenia with predisposition to acute lymphoblastic leukemia. Haematologica, 101(11):1333–1342, June 2016. URL: http://dx.doi.org/10.3324/haematol.2016.147496, doi:10.3324/haematol.2016.147496. This article has 87 citations.](https://doi.org/10.3324/haematol.2016.147496)

[9. (Montpetit2001Comparative) Alexandre Montpetit and Daniel Sinnett. Comparative analysis of the etv6 gene in vertebrate genomes from pufferfish to human. Oncogene, 20(26):3437–3442, June 2001. URL: http://dx.doi.org/10.1038/sj.onc.1204444, doi:10.1038/sj.onc.1204444. This article has 8 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1038/sj.onc.1204444)

[10. (Boccuni2003The) Piernicola Boccuni, Donal MacGrogan, Joseph M. Scandura, and Stephen D. Nimer. The human l(3)mbt polycomb group protein is a transcriptional repressor and interacts physically and functionally with tel (etv6). Journal of Biological Chemistry, 278(17):15412–15420, April 2003. URL: http://dx.doi.org/10.1074/JBC.M300592200, doi:10.1074/jbc.m300592200. This article has 144 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/JBC.M300592200)

[11. (Gerak2021Biophysical) Chloe A.N. Gerak, Sophia Y. Cho, Maxim Kolesnikov, Mark Okon, Michael E.P. Murphy, Richard B. Sessions, Michel Roberge, and Lawrence P. McIntosh. Biophysical characterization of the etv6 pnt domain polymerization interfaces. Journal of Biological Chemistry, 296:100284, January 2021. URL: http://dx.doi.org/10.1016/j.jbc.2021.100284, doi:10.1016/j.jbc.2021.100284. This article has 4 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1016/j.jbc.2021.100284)

[12. (Biswas2020ETV6) Angana Biswas, Yetirajam Rajesh, Pralay Mitra, and Mahitosh Mandal. Etv6 gene aberrations in non-haematological malignancies: a review highlighting etv6 associated fusion genes in solid tumors. Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, 1874(1):188389, August 2020. URL: http://dx.doi.org/10.1016/j.bbcan.2020.188389, doi:10.1016/j.bbcan.2020.188389. This article has 14 citations.](https://doi.org/10.1016/j.bbcan.2020.188389)

[13. (De2014ETV6) Braekeleer E De, N Douet-Guilbert, and Braekeleer M De. Etv6 (ets variant 6). Atlas of Genetics and Cytogenetics in Oncology and Haematology, November 2014. URL: http://dx.doi.org/10.4267/2042/54367, doi:10.4267/2042/54367. This article has 0 citations and is from a peer-reviewed journal.](https://doi.org/10.4267/2042/54367)

[14. (Noetzli2015Germline) Leila Noetzli, Richard W Lo, Alisa B Lee-Sherick, Michael Callaghan, Patrizia Noris, Anna Savoia, Madhvi Rajpurkar, Kenneth Jones, Katherine Gowan, Carlo L Balduini, Alessandro Pecci, Chiara Gnan, Daniela De Rocco, Michael Doubek, Ling Li, Lily Lu, Richard Leung, Carolina Landolt-Marticorena, Stephen Hunger, Paula Heller, Arthur Gutierrez-Hartmann, Liang Xiayuan, Fred G Pluthero, Jesse W Rowley, Andrew S Weyrich, Walter H A Kahr, Christopher C Porter, and Jorge Di Paola. Germline mutations in etv6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia. Nature Genetics, 47(5):535–538, March 2015. URL: http://dx.doi.org/10.1038/ng.3253, doi:10.1038/ng.3253. This article has 262 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/ng.3253)

[15. (Hock2017ETV6) Hanno Hock and Akiko Shimamura. Etv6 in hematopoiesis and leukemia predisposition. Seminars in Hematology, 54(2):98–104, April 2017. URL: http://dx.doi.org/10.1053/j.seminhematol.2017.04.005, doi:10.1053/j.seminhematol.2017.04.005. This article has 90 citations and is from a peer-reviewed journal.](https://doi.org/10.1053/j.seminhematol.2017.04.005)

[16. (De2014Steric) Soumya De, Anson C.K. Chan, H. Jerome Coyne, Niraja Bhachech, Ulrike Hermsdorf, Mark Okon, Michael E.P. Murphy, Barbara J. Graves, and Lawrence P. McIntosh. Steric mechanism of auto-inhibitory regulation of specific and non-specific dna binding by the ets transcriptional repressor etv6. Journal of Molecular Biology, 426(7):1390–1406, April 2014. URL: http://dx.doi.org/10.1016/j.jmb.2013.11.031, doi:10.1016/j.jmb.2013.11.031. This article has 63 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1016/j.jmb.2013.11.031)