FOXO1 forkhead domain mutants in B-cell lymphoma lack transcriptional activity.
(2022) Scientific Reports — Vol. 12, n° 1, p. 1309 (2022)
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- 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.
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Sablon, A., Bollaert, E., Pirson, C., Velghe, A., & Demoulin, J. B. (2022). FOXO1 forkhead domain mutants in B-cell lymphoma lack transcriptional activity. Scientific Reports, 12(1), 1309. https://doi.org/10.1038/s41598-022-05334-4 (Original work published 2022)