FoxO1 signaling in B cell malignancies and its therapeutic targeting.

IF 3.5 4区生物学 Q1 Biochemistry, Genetics and Molecular Biology

FEBS Letters Pub Date : 2024-11-12 DOI:10.1002/1873-3468.15057

Krystof Hlavac, Petra Pavelkova, Laura Ondrisova, Marek Mraz

{"title":"FoxO1 signaling in B cell malignancies and its therapeutic targeting.","authors":"Krystof Hlavac, Petra Pavelkova, Laura Ondrisova, Marek Mraz","doi":"10.1002/1873-3468.15057","DOIUrl":null,"url":null,"abstract":"<p><p>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).</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5000,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"FEBS Letters","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1002/1873-3468.15057","RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"Biochemistry, Genetics and Molecular Biology","Score":null,"Total":0}

引用次数: 0

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).

查看原文本刊更多论文

B 细胞恶性肿瘤中的 FoxO1 信号转导及其治疗靶点。

FoxO 转录因子（FoxO1、FoxO3a、FoxO4、FoxO6）是 "叉头 "盒蛋白亚家族中一个高度进化保守的亚家族。它们历来被认为是肿瘤抑制因子，但 FoxO1 也具有致癌特性。FoxO1 在 B 细胞发育和分化、免疫球蛋白基因重排和细胞表面 B 细胞受体（BCR）结构、DNA 损伤控制、细胞周期调控和生殖中心反应中的各种作用说明了 FoxO1 的复杂性。FoxO1 在转录水平（STAT3、HEB、EBF、FoxOs）和转录后水平（Akt、AMPK、CDK2、GSK3、IKKs、JNK、MAPK/Erk、SGK1、miRNA）受到严格调控。在 B 细胞恶性肿瘤中，FoxO1 的活化突变（S22/T24）和异常核输出及活性反复出现，这突显了其治疗抑制的潜力。在此，我们回顾了 FoxO1 在 B 细胞和髓系恶性肿瘤中的作用，即急性淋巴细胞白血病（ALL）、急性髓系白血病（AML）、慢性淋巴细胞白血病（CLL）、滤泡性淋巴瘤（FL）、弥漫大 B 细胞淋巴瘤（DLBCL）、套细胞淋巴瘤（MCL）、伯基特淋巴瘤（BL）、霍奇金淋巴瘤（HL）和多发性骨髓瘤（MM）。我们还讨论了目前可用的抑制剂（AS1708727、AS1842856、cpd10）靶向 FoxO1 的临床前证据。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

FEBS Letters 生物-生化与分子生物学

CiteScore

7.00

自引率

2.90%

发文量

303

审稿时长

1.0 months

期刊介绍： FEBS Letters is one of the world''s leading journals in molecular biology and is renowned both for its quality of content and speed of production. Bringing together the most important developments in the molecular biosciences, FEBS Letters provides an international forum for Minireviews, Research Letters and Hypotheses that merit urgent publication.