Role of FOXO1 mutations in the pathogenesis of B cell non-Hodgkin lymphomas

FOXO1突变在B细胞非霍奇金淋巴瘤发病机制中的作用

• 批准号: 10334435
• 负责人: David Dominguez-Sola
• 金额: $ 37.77万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-05 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10334435
• 关键词: AKT Signaling Pathway; Address; Adoptive Transfer; Affinity; Alleles; Animal Model; Automobile Driving; B cell differentiation; B-Cell Antigen Receptor; B-Cell Development; B-Cell Lymphomas; B-Cell NonHodgkins Lymphoma; B-Lymphocytes; Biological; Biological Assay; Biological Process; Biology; Burkitt Lymphoma; Cancerous; Cell Line; Cells; Characteristics; Chimera organism; Classification; Clonal Expansion; Diffuse; Disease Progression; Engineering; Event; Exclusion; FOXO1A gene; Family; Foxes; Genes; Genetic; Genetic Transcription; Goals; Homeostasis; Human; Immune signaling; Immunoglobulin Class Switching; Immunoglobulin Somatic Hypermutation; Immunoglobulin Switch Recombination; In Vitro; Light; Link; Lymphoid; Lymphoma; Lymphomagenesis; Maintenance; Malignant - descriptor; Malignant Neoplasms; Malignant lymphoid neoplasm; Measures; Mediator of activation protein; Missense Mutation; Molecular; Mus; Mutation; Mutation Analysis; Nuclear; Nuclear Export; Outcome; PI3K/AKT; Pathogenesis; Pathway interactions; Physiology; Pre-Clinical Model; Prognostic Factor; Recurrence; Regulation; Relapse; Research Proposals; Role; Sampling; Signal Transduction; Site; Somatic Mutation; Structure of germinal center of lymph node; T-Lymphocyte; Testing; Therapeutic; Therapeutic Agents; Tumor Suppressor Proteins; Validation; Variant; base; cancer type; cell transformation; cellular engineering; chemical genetics; clinically relevant; forkhead protein; genetic approach; genome-wide; improved; in vivo; inhibitor; insight; interest; large cell Diffuse non-Hodgkin' s lymphoma; member; mutant; novel; novel therapeutic intervention; programs; response; stress activated protein kinase; transcription factor

Project Summary/Abstract A fraction of germinal center-derived B cell non-Hodgkin lymphomas (~12% of Burkitt lymphomas, ~9% of Diffuse Large B cell lymphomas, up to 36% of relapsed Diffuse Large B cell lymphoma cases) carry recurrent missense mutations in FOXO1, a member of the Fox-O family of Forkhead transcription factors. FOXO1 controls critical stage transitions during B cell development, and is a main target of the PI3K/AKT pathway, which relays key survival signals downstream of the B cell receptor. While FOXO1 is inactivated and thus classically regarded as a tumor suppressor in diverse cancer types and in animal models, lymphoma- associated FOXO1 mutations are predicted instead to lock FOXO1 in a constitutively active state by rendering it insensitive to PI3K-dependent nuclear export and degradation. In a recent study we found that FOXO1 is critical for the maintenance of specific B cell fate programs required for the control of zonal polarity in the germinal center. Consistently, FOXO1 null germinal centers fail to support some key biological functions that are typically associated to zonal polarity, including affinity maturation and class-switch recombination. This project seeks to understand how lymphoma-associated mutations impact FOXO1 activities in germinal center B cells, and how these events may contribute to the pathogenesis of germinal center-derived B cell non-Hodgkin lymphomas. We propose that FOXO1 mutations actively contribute to B cell lymphomagenesis by altering the control of germinal center polarity and B cell responses to specific immune signals. To test this idea, we will develop the following specific aims: 1) Investigate how FOXO1 mutations alter B cell responses driven by stress-activated protein kinase pathways, combining in vitro and in vivo chemical genetics strategies in normal, cancerous germinal center B cells to measure and manipulate FOXO1 responses to these specific pathways; with further validation through the analysis of primary B-NHL cases; 2) Determine the impact of FOXO1 mutations on germinal center B-cell homeostasis, by engineering germinal center B cells with specific missense mutations in order to evaluate their effects on germinal center polarity and the control of germinal center-specific FOXO1 transcriptional programs; 3) Evaluate the role of FOXO1 mutations in the pathogenesis of MYC-driven B-cell lymphomas, by using adoptive transfer strategies to mimic in vivo the genetics of a fraction (~12%) of Burkitt lymphomas in which MYC deregulation and FOXO1 mutations coexist. Given the role of FOXO1 in normal germinal center physiology, the results of this study are expected to provide direct insights into cellular and molecular mechanisms involved in the pathogenesis of germinal center-derived B cell non-Hodgkin lymphomas. These studies are likely to be clinically relevant because of the growing interest on PI3K inhibitors as therapeutic agents in this group of malignancies.

项目摘要/摘要 生发中心起源的B细胞非霍奇金淋巴瘤的一部分(~12%的Burkitt淋巴瘤，~9%的Burkitt淋巴瘤 弥漫性大B细胞淋巴瘤，高达36%的复发弥漫性大B细胞淋巴瘤病例) FOXO1的错义突变，FOXO1是Fox-O叉头转录因子家族的成员。Foxo1 控制B细胞发育过程中的关键阶段转变，是PI3K/AKT通路的主要靶点， 它在B细胞受体下游传递关键的生存信号。而FOXO1被停用，因此 在各种癌症类型和动物模型中，淋巴瘤被经典地视为肿瘤抑制因子- 相反，相关的FOXO1突变被预测为通过呈现将FOXO1锁定在结构性活动状态 它对依赖PI3K的核输出和降解不敏感。 在最近的一项研究中，我们发现FOXO1对于维持所需的特定B细胞命运程序至关重要 用于控制生发中心的纬向极性。一直以来，FOXO1零生发中心无法支持 一些关键的生物功能，通常与地带性极性有关，包括亲和力成熟和 类交换重组。这个项目试图了解淋巴瘤相关突变是如何影响 Foxo1在生发中心B细胞中的活性，以及这些事件可能如何在糖尿病的发病机制中起作用。 生发中心衍生的B细胞非霍奇金淋巴瘤。我们认为FOXO1突变对 通过改变生发中心极性的控制和B细胞对特异性的反应来促进B细胞淋巴瘤的发生 免疫信号。 为了验证这一想法，我们将制定以下具体目标：1)研究FOXO1突变如何改变B细胞 应激激活蛋白激酶通路驱动的反应，结合体外和体内化学遗传学 在正常的、癌变的生发中心B细胞中测量和操纵FOXO1对这些反应的策略 具体途径；通过对原发B-NHL病例的分析进一步验证；2)确定 通过改造生发中心B细胞，FOXO1突变对生发中心B细胞稳态的影响 以评估其对生发中心极性的影响和对疾病的控制 生发中心特异的FOXO1转录程序；3)评估FOXO1突变在 利用过继转移策略在体内模拟MYC驱动的B细胞淋巴瘤的发病机制 部分(~12%)Burkitt淋巴瘤MYC基因缺失和FOXO1突变共存的遗传学研究 鉴于FOXO1在正常生发中心生理中的作用，这项研究的结果有望提供 直接洞察生发中心衍生疾病发病的细胞和分子机制 B细胞性非霍奇金淋巴瘤。这些研究可能具有临床相关性，因为越来越多的 对PI3K抑制剂作为治疗药物在这组恶性肿瘤中的兴趣。