FOXO1 forkhead domain mutants in B-cell lymphoma lack transcriptional activity
Abstract Somatic point mutations of the FOXO1 transcription factor were reported in non-Hodgkin lymphoma including diffuse large B-cell lymphoma, follicular lymphoma and Burkitt lymphoma. These alterations were associated with a poor prognosis and resistance to therapy. Nearly all amino acid substit...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2022-01-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-05334-4 |
| _version_ | 1819280421104386048 |
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| author | Ariane Sablon Emeline Bollaert Constance Pirson Amélie I. Velghe Jean-Baptiste Demoulin |
| author_facet | Ariane Sablon Emeline Bollaert Constance Pirson Amélie I. Velghe Jean-Baptiste Demoulin |
| author_sort | Ariane Sablon |
| collection | DOAJ |
| description | Abstract Somatic point mutations of the FOXO1 transcription factor were reported in non-Hodgkin lymphoma including diffuse large B-cell lymphoma, follicular lymphoma and Burkitt lymphoma. These alterations were associated with a poor prognosis and resistance to therapy. Nearly all amino acid substitutions are localized in two major clusters, affecting either the N-terminal region (Nt mutations) or the forkhead DNA-binding domain (DBD mutations). While recent studies have focused on Nt mutations, we characterized FOXO1 DBD mutants. We analyzed their transcriptional activity, DNA binding, phosphorylation and protein–protein interaction. The majority of DBD mutants showed a decrease in activity and DNA binding, while preserving AKT phosphorylation and interaction with the cytoplasmic ATG7 protein. In addition, we investigated the importance of conserved residues of the α-helix 3 of the DBD. Amino acids I213, R214, H215 and L217 appeared to be crucial for FOXO1 activity. Our data underlined the key role of multiple amino-acid residues of the forkhead domain in FOXO1 transcriptional activity and revealed a new type of FOXO1 loss-of-function mutations in B-cell lymphoma. |
| first_indexed | 2024-12-24T00:43:31Z |
| format | Article |
| id | doaj.art-b2bb925e220f47229c85166c558a5977 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-24T00:43:31Z |
| publishDate | 2022-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-b2bb925e220f47229c85166c558a59772022-12-21T17:23:53ZengNature PortfolioScientific Reports2045-23222022-01-011211710.1038/s41598-022-05334-4FOXO1 forkhead domain mutants in B-cell lymphoma lack transcriptional activityAriane Sablon0Emeline Bollaert1Constance Pirson2Amélie I. Velghe3Jean-Baptiste Demoulin4Experimental Medicine Unit, De Duve Institute, Université Catholique de LouvainExperimental Medicine Unit, De Duve Institute, Université Catholique de LouvainExperimental Medicine Unit, De Duve Institute, Université Catholique de LouvainExperimental Medicine Unit, De Duve Institute, Université Catholique de LouvainExperimental Medicine Unit, De Duve Institute, Université Catholique de LouvainAbstract Somatic point mutations of the FOXO1 transcription factor were reported in non-Hodgkin lymphoma including diffuse large B-cell lymphoma, follicular lymphoma and Burkitt lymphoma. These alterations were associated with a poor prognosis and resistance to therapy. Nearly all amino acid substitutions are localized in two major clusters, affecting either the N-terminal region (Nt mutations) or the forkhead DNA-binding domain (DBD mutations). While recent studies have focused on Nt mutations, we characterized FOXO1 DBD mutants. We analyzed their transcriptional activity, DNA binding, phosphorylation and protein–protein interaction. The majority of DBD mutants showed a decrease in activity and DNA binding, while preserving AKT phosphorylation and interaction with the cytoplasmic ATG7 protein. In addition, we investigated the importance of conserved residues of the α-helix 3 of the DBD. Amino acids I213, R214, H215 and L217 appeared to be crucial for FOXO1 activity. Our data underlined the key role of multiple amino-acid residues of the forkhead domain in FOXO1 transcriptional activity and revealed a new type of FOXO1 loss-of-function mutations in B-cell lymphoma.https://doi.org/10.1038/s41598-022-05334-4 |
| spellingShingle | Ariane Sablon Emeline Bollaert Constance Pirson Amélie I. Velghe Jean-Baptiste Demoulin FOXO1 forkhead domain mutants in B-cell lymphoma lack transcriptional activity Scientific Reports |
| title | FOXO1 forkhead domain mutants in B-cell lymphoma lack transcriptional activity |
| title_full | FOXO1 forkhead domain mutants in B-cell lymphoma lack transcriptional activity |
| title_fullStr | FOXO1 forkhead domain mutants in B-cell lymphoma lack transcriptional activity |
| title_full_unstemmed | FOXO1 forkhead domain mutants in B-cell lymphoma lack transcriptional activity |
| title_short | FOXO1 forkhead domain mutants in B-cell lymphoma lack transcriptional activity |
| title_sort | foxo1 forkhead domain mutants in b cell lymphoma lack transcriptional activity |
| url | https://doi.org/10.1038/s41598-022-05334-4 |
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