Inherited Thrombocytopenia Related Genes: GPS2 Mediates the Interplay Between ANKRD26 and ETV6
Mutations in the genes <i>ANKRD26</i>, <i>RUNX1</i>, and <i>ETV6</i> cause three clinically overlapping thrombocytopenias characterized by a predisposition to hematological neoplasms. The <i>ANKRD26</i> gene, which encodes a protein involved in protein...
Saved in:
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2024-12-01
|
| Series: | Cells |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2073-4409/14/1/23 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1841549290558717952 |
|---|---|
| author | Valeria Capaci Melania Eva Zanchetta Giorgia Fontana Daniele Ammeti Roberta Bottega Michela Faleschini Anna Savoia |
| author_facet | Valeria Capaci Melania Eva Zanchetta Giorgia Fontana Daniele Ammeti Roberta Bottega Michela Faleschini Anna Savoia |
| author_sort | Valeria Capaci |
| collection | DOAJ |
| description | Mutations in the genes <i>ANKRD26</i>, <i>RUNX1</i>, and <i>ETV6</i> cause three clinically overlapping thrombocytopenias characterized by a predisposition to hematological neoplasms. The <i>ANKRD26</i> gene, which encodes a protein involved in protein-protein interactions, is downregulated by RUNX1 during megakaryopoiesis. Mutations in 5′UTR of ANKRD26, leading to ANKRD26-RT, disrupt this regulation, resulting in the persistent expression of ANKRD26, which leads to impaired platelet biogenesis and an increased risk of leukemia. Although ANKRD26 and ETV6 exhibit inverse expression during megakaryopoiesis, ETV6 does not regulate the ANKRD26 expression. Hypothesizing an interplay between ETV6 and ANKRD26 through in vitro studies, we explored the interactions between the two proteins. In this study, we found that ANKRD26 interacts with ETV6 and retains it in the cytoplasm, phenocopying ETV6-RT-related mutants. We found that GPS2, a component of the NCoR complex, binds both ANKRD26 and ETV6, mediating this interaction. Furthermore, ANKRD26 overexpression deregulates ETV6 transcriptional repression, supporting a common pathogenic mechanism underlying ANKRD26-RT, FPD/AML, and ETV6-RT. Our results unveil a novel ANKRD26-ETV6-GPS2 axis, providing new insights to investigate the molecular mechanism underlying thrombocytopenias with a predisposition to myeloid neoplasms that need to be further characterized. |
| format | Article |
| id | doaj-art-a336aec4c9c5498e9012032e15f0eb3e |
| institution | Kabale University |
| issn | 2073-4409 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj-art-a336aec4c9c5498e9012032e15f0eb3e2025-01-10T13:16:17ZengMDPI AGCells2073-44092024-12-011412310.3390/cells14010023Inherited Thrombocytopenia Related Genes: GPS2 Mediates the Interplay Between ANKRD26 and ETV6Valeria Capaci0Melania Eva Zanchetta1Giorgia Fontana2Daniele Ammeti3Roberta Bottega4Michela Faleschini5Anna Savoia6Institute for Maternal and Child Health, IRCCS Burlo Garofolo, 34137 Trieste, ItalyInstitute for Maternal and Child Health, IRCCS Burlo Garofolo, 34137 Trieste, ItalyInstitute for Maternal and Child Health, IRCCS Burlo Garofolo, 34137 Trieste, ItalyInstitute for Maternal and Child Health, IRCCS Burlo Garofolo, 34137 Trieste, ItalyInstitute for Maternal and Child Health, IRCCS Burlo Garofolo, 34137 Trieste, ItalyInstitute for Maternal and Child Health, IRCCS Burlo Garofolo, 34137 Trieste, ItalyDepartment of Neurosciences, Biomedicine and Movement Sciences, University of Verona, 37134 Verona, ItalyMutations in the genes <i>ANKRD26</i>, <i>RUNX1</i>, and <i>ETV6</i> cause three clinically overlapping thrombocytopenias characterized by a predisposition to hematological neoplasms. The <i>ANKRD26</i> gene, which encodes a protein involved in protein-protein interactions, is downregulated by RUNX1 during megakaryopoiesis. Mutations in 5′UTR of ANKRD26, leading to ANKRD26-RT, disrupt this regulation, resulting in the persistent expression of ANKRD26, which leads to impaired platelet biogenesis and an increased risk of leukemia. Although ANKRD26 and ETV6 exhibit inverse expression during megakaryopoiesis, ETV6 does not regulate the ANKRD26 expression. Hypothesizing an interplay between ETV6 and ANKRD26 through in vitro studies, we explored the interactions between the two proteins. In this study, we found that ANKRD26 interacts with ETV6 and retains it in the cytoplasm, phenocopying ETV6-RT-related mutants. We found that GPS2, a component of the NCoR complex, binds both ANKRD26 and ETV6, mediating this interaction. Furthermore, ANKRD26 overexpression deregulates ETV6 transcriptional repression, supporting a common pathogenic mechanism underlying ANKRD26-RT, FPD/AML, and ETV6-RT. Our results unveil a novel ANKRD26-ETV6-GPS2 axis, providing new insights to investigate the molecular mechanism underlying thrombocytopenias with a predisposition to myeloid neoplasms that need to be further characterized.https://www.mdpi.com/2073-4409/14/1/23ANKRD26ETV6GPS2hematological neoplasmsthrombocytopenia |
| spellingShingle | Valeria Capaci Melania Eva Zanchetta Giorgia Fontana Daniele Ammeti Roberta Bottega Michela Faleschini Anna Savoia Inherited Thrombocytopenia Related Genes: GPS2 Mediates the Interplay Between ANKRD26 and ETV6 Cells ANKRD26 ETV6 GPS2 hematological neoplasms thrombocytopenia |
| title | Inherited Thrombocytopenia Related Genes: GPS2 Mediates the Interplay Between ANKRD26 and ETV6 |
| title_full | Inherited Thrombocytopenia Related Genes: GPS2 Mediates the Interplay Between ANKRD26 and ETV6 |
| title_fullStr | Inherited Thrombocytopenia Related Genes: GPS2 Mediates the Interplay Between ANKRD26 and ETV6 |
| title_full_unstemmed | Inherited Thrombocytopenia Related Genes: GPS2 Mediates the Interplay Between ANKRD26 and ETV6 |
| title_short | Inherited Thrombocytopenia Related Genes: GPS2 Mediates the Interplay Between ANKRD26 and ETV6 |
| title_sort | inherited thrombocytopenia related genes gps2 mediates the interplay between ankrd26 and etv6 |
| topic | ANKRD26 ETV6 GPS2 hematological neoplasms thrombocytopenia |
| url | https://www.mdpi.com/2073-4409/14/1/23 |
| work_keys_str_mv | AT valeriacapaci inheritedthrombocytopeniarelatedgenesgps2mediatestheinterplaybetweenankrd26andetv6 AT melaniaevazanchetta inheritedthrombocytopeniarelatedgenesgps2mediatestheinterplaybetweenankrd26andetv6 AT giorgiafontana inheritedthrombocytopeniarelatedgenesgps2mediatestheinterplaybetweenankrd26andetv6 AT danieleammeti inheritedthrombocytopeniarelatedgenesgps2mediatestheinterplaybetweenankrd26andetv6 AT robertabottega inheritedthrombocytopeniarelatedgenesgps2mediatestheinterplaybetweenankrd26andetv6 AT michelafaleschini inheritedthrombocytopeniarelatedgenesgps2mediatestheinterplaybetweenankrd26andetv6 AT annasavoia inheritedthrombocytopeniarelatedgenesgps2mediatestheinterplaybetweenankrd26andetv6 |