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.
Highlights
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
Our results revealed the existence of FOXO1 loss-of-function mutations in non-Hodgkin lymphoma, suggesting that FOXO1 plays a complex role in this disease
Nt mutations and six DBD mutations among those initially reported by Trinh et al in diffuse large B-cell lymphoma (DLBCL) and Pasqualucci et al in follicular lymphoma based on amino acid conservation and predicted damage[8,11] (Fig. 1A and Table 1)
Summary
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. 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. 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. AKT directly phosphorylates FOXO1 on three different sites (Thr[24], Ser[256], Ser319), leading to its transcriptional inactivation by nuclear e xport[1] In line with these cellular activities and regulations, FOXO1 loss-of-function alterations have been reported in numerous cancer types, including classical Hodgkin lymphoma[2]. Our results revealed the existence of FOXO1 loss-of-function mutations in non-Hodgkin lymphoma, suggesting that FOXO1 plays a complex role in this disease
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