Functional Classification of Fusion Proteins in Sarcoma
Sarcomas comprise a heterogeneous group of malignant tumors of mesenchymal origin. More than 80 entities are associated with different mesenchymal lineages. Sarcomas with fibroblastic, muscle, bone, vascular, adipocytic, and other characteristics are distinguished. Nearly half of all entities contai...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2024-03-01
|
| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/16/7/1355 |
| _version_ | 1797212794079150080 |
|---|---|
| author | Marco Wachtel Didier Surdez Thomas G. P. Grünewald Beat W. Schäfer |
| author_facet | Marco Wachtel Didier Surdez Thomas G. P. Grünewald Beat W. Schäfer |
| author_sort | Marco Wachtel |
| collection | DOAJ |
| description | Sarcomas comprise a heterogeneous group of malignant tumors of mesenchymal origin. More than 80 entities are associated with different mesenchymal lineages. Sarcomas with fibroblastic, muscle, bone, vascular, adipocytic, and other characteristics are distinguished. Nearly half of all entities contain specific chromosomal translocations that give rise to fusion proteins. These are mostly pathognomonic, and their detection by various molecular techniques supports histopathologic classification. Moreover, the fusion proteins act as oncogenic drivers, and their blockade represents a promising therapeutic approach. This review summarizes the current knowledge on fusion proteins in sarcoma. We categorize the different fusion proteins into functional classes, including kinases, epigenetic regulators, and transcription factors, and describe their mechanisms of action. Interestingly, while fusion proteins acting as transcription factors are found in all mesenchymal lineages, the others have a more restricted pattern. Most kinase-driven sarcomas belong to the fibroblastic/myofibroblastic lineage. Fusion proteins with an epigenetic function are mainly associated with sarcomas of unclear differentiation, suggesting that epigenetic dysregulation leads to a major change in cell identity. Comparison of mechanisms of action reveals recurrent functional modes, including antagonism of Polycomb activity by fusion proteins with epigenetic activity and recruitment of histone acetyltransferases by fusion transcription factors of the myogenic lineage. Finally, based on their biology, we describe potential approaches to block the activity of fusion proteins for therapeutic intervention. Overall, our work highlights differences as well as similarities in the biology of fusion proteins from different sarcomas and provides the basis for a functional classification. |
| first_indexed | 2024-04-24T10:48:02Z |
| format | Article |
| id | doaj.art-9fb7ad993e304741a096ff89457f7646 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-04-24T10:48:02Z |
| publishDate | 2024-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-9fb7ad993e304741a096ff89457f76462024-04-12T13:16:07ZengMDPI AGCancers2072-66942024-03-01167135510.3390/cancers16071355Functional Classification of Fusion Proteins in SarcomaMarco Wachtel0Didier Surdez1Thomas G. P. Grünewald2Beat W. Schäfer3Department of Oncology and Children’s Research Center, University Children’s Hospital, Steinwiesstrasse 75, CH-8032 Zurich, SwitzerlandBalgrist University Hospital, Faculty of Medicine, University of Zurich (UZH), CH-8008 Zurich, SwitzerlandDivision of Translational Pediatric Sarcoma Research, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), 69120 Heidelberg, GermanyDepartment of Oncology and Children’s Research Center, University Children’s Hospital, Steinwiesstrasse 75, CH-8032 Zurich, SwitzerlandSarcomas comprise a heterogeneous group of malignant tumors of mesenchymal origin. More than 80 entities are associated with different mesenchymal lineages. Sarcomas with fibroblastic, muscle, bone, vascular, adipocytic, and other characteristics are distinguished. Nearly half of all entities contain specific chromosomal translocations that give rise to fusion proteins. These are mostly pathognomonic, and their detection by various molecular techniques supports histopathologic classification. Moreover, the fusion proteins act as oncogenic drivers, and their blockade represents a promising therapeutic approach. This review summarizes the current knowledge on fusion proteins in sarcoma. We categorize the different fusion proteins into functional classes, including kinases, epigenetic regulators, and transcription factors, and describe their mechanisms of action. Interestingly, while fusion proteins acting as transcription factors are found in all mesenchymal lineages, the others have a more restricted pattern. Most kinase-driven sarcomas belong to the fibroblastic/myofibroblastic lineage. Fusion proteins with an epigenetic function are mainly associated with sarcomas of unclear differentiation, suggesting that epigenetic dysregulation leads to a major change in cell identity. Comparison of mechanisms of action reveals recurrent functional modes, including antagonism of Polycomb activity by fusion proteins with epigenetic activity and recruitment of histone acetyltransferases by fusion transcription factors of the myogenic lineage. Finally, based on their biology, we describe potential approaches to block the activity of fusion proteins for therapeutic intervention. Overall, our work highlights differences as well as similarities in the biology of fusion proteins from different sarcomas and provides the basis for a functional classification.https://www.mdpi.com/2072-6694/16/7/1355sarcomafusion proteinstranscription factorskinasesepigenetic regulatorsmesenchymal lineage |
| spellingShingle | Marco Wachtel Didier Surdez Thomas G. P. Grünewald Beat W. Schäfer Functional Classification of Fusion Proteins in Sarcoma Cancers sarcoma fusion proteins transcription factors kinases epigenetic regulators mesenchymal lineage |
| title | Functional Classification of Fusion Proteins in Sarcoma |
| title_full | Functional Classification of Fusion Proteins in Sarcoma |
| title_fullStr | Functional Classification of Fusion Proteins in Sarcoma |
| title_full_unstemmed | Functional Classification of Fusion Proteins in Sarcoma |
| title_short | Functional Classification of Fusion Proteins in Sarcoma |
| title_sort | functional classification of fusion proteins in sarcoma |
| topic | sarcoma fusion proteins transcription factors kinases epigenetic regulators mesenchymal lineage |
| url | https://www.mdpi.com/2072-6694/16/7/1355 |
| work_keys_str_mv | AT marcowachtel functionalclassificationoffusionproteinsinsarcoma AT didiersurdez functionalclassificationoffusionproteinsinsarcoma AT thomasgpgrunewald functionalclassificationoffusionproteinsinsarcoma AT beatwschafer functionalclassificationoffusionproteinsinsarcoma |