FoxO1 signaling in B cell malignancies and its therapeutic targeting.

in FEBS letters by Krystof Hlavac, Petra Pavelkova, Laura Ondrisova, Marek Mraz

TLDR

  • FoxO transcription factors (FoxO1, FoxO3a, FoxO4, FoxO6) are a group of proteins that play important roles in various cellular processes, including B cell development and differentiation, immunoglobulin gene rearrangement and cell-surface B cell receptor (BCR) structure, DNA damage control, cell cycle regulation, and germinal center reaction. These proteins have traditionally been considered tumor suppressors, but FoxO1 also exhibits oncogenic properties. The study reviews FoxO1's roles across B cell and myeloid malignancies, including ALL, AML, CLL, FL, DLBCL, MCL, BL, HL, and MM. The findings suggest that FoxO1 plays a crucial role in these malignancies, and the study highlights the potential of FoxO1 as a therapeutic target. The study's findings have significant implications for the field of research and clinical practice, as they provide a comprehensive understanding of FoxO1's roles in various B cell and myeloid malignancies. The study also highlights the potential of FoxO1 as a therapeutic target, with recurrent FoxO1 activating mutations (S22/T24) and aberrant nuclear export and activity having been described. Future research directions could include the development of more specific and effective FoxO1 inhibitors, as well as the exploration of FoxO1's roles in other types of cancer. Additionally, the study could be expanded to include other types of malignancies beyond B cell and myeloid cancers to further elucidate FoxO1's roles and potential as a therapeutic target.

Abstract

FoxO transcription factors (FoxO1, FoxO3a, FoxO4, FoxO6) are a highly evolutionary conserved subfamily of the 'forkhead' box proteins. They have traditionally been considered tumor suppressors, but FoxO1 also exhibits oncogenic properties. The complex nature of FoxO1 is illustrated by its various roles in B cell development and differentiation, immunoglobulin gene rearrangement and cell-surface B cell receptor (BCR) structure, DNA damage control, cell cycle regulation, and germinal center reaction. FoxO1 is tightly regulated at a transcriptional (STAT3, HEB, EBF, FoxOs) and post-transcriptional level (Akt, AMPK, CDK2, GSK3, IKKs, JNK, MAPK/Erk, SGK1, miRNA). In B cell malignancies, recurrent FoxO1 activating mutations (S22/T24) and aberrant nuclear export and activity have been described, underscoring the potential of its therapeutic inhibition. Here, we review FoxO1's roles across B cell and myeloid malignancies, namely acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Burkitt lymphoma (BL), Hodgkin lymphoma (HL), and multiple myeloma (MM). We also discuss preclinical evidence for FoxO1 targeting by currently available inhibitors (AS1708727, AS1842856, cpd10).

Overview

  • FoxO transcription factors (FoxO1, FoxO3a, FoxO4, FoxO6) are a highly evolutionary conserved subfamily of the 'forkhead' box proteins. They have traditionally been considered tumor suppressors, but FoxO1 also exhibits oncogenic properties. The complex nature of FoxO1 is illustrated by its various roles in B cell development and differentiation, immunoglobulin gene rearrangement and cell-surface B cell receptor (BCR) structure, DNA damage control, cell cycle regulation, and germinal center reaction. FoxO1 is tightly regulated at a transcriptional (STAT3, HEB, EBF, FoxOs) and post-transcriptional level (Akt, AMPK, CDK2, GSK3, IKKs, JNK, MAPK/Erk, SGK1, miRNA). In B cell malignancies, recurrent FoxO1 activating mutations (S22/T24) and aberrant nuclear export and activity have been described, underscoring the potential of its therapeutic inhibition. The study aims to review FoxO1's roles across B cell and myeloid malignancies, namely acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Burkitt lymphoma (BL), Hodgkin lymphoma (HL), and multiple myeloma (MM). The primary objective is to provide a comprehensive understanding of FoxO1's roles in these malignancies and its potential as a therapeutic target.

Comparative Analysis & Findings

  • The study compares the roles of FoxO1 across various B cell and myeloid malignancies, including ALL, AML, CLL, FL, DLBCL, MCL, BL, HL, and MM. The results show that FoxO1 plays a crucial role in B cell development and differentiation, immunoglobulin gene rearrangement and cell-surface B cell receptor (BCR) structure, DNA damage control, cell cycle regulation, and germinal center reaction. The study also highlights the potential of FoxO1 as a therapeutic target in these malignancies, with recurrent FoxO1 activating mutations (S22/T24) and aberrant nuclear export and activity having been described. The findings suggest that FoxO1 inhibition could be a promising therapeutic approach for these malignancies.

Implications and Future Directions

  • The study's findings have significant implications for the field of research and clinical practice, as they provide a comprehensive understanding of FoxO1's roles in various B cell and myeloid malignancies. The study also highlights the potential of FoxO1 as a therapeutic target, with recurrent FoxO1 activating mutations (S22/T24) and aberrant nuclear export and activity having been described. Future research directions could include the development of more specific and effective FoxO1 inhibitors, as well as the exploration of FoxO1's roles in other types of cancer. Additionally, the study could be expanded to include other types of malignancies beyond B cell and myeloid cancers to further elucidate FoxO1's roles and potential as a therapeutic target.
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