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: 10087895
• 负责人: David Dominguez-Sola
• 金额: $ 38.54万
• 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 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10087895
• 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/antagonist; 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.

项目总结/摘要 一部分生发中心来源的B细胞非霍奇金淋巴瘤（伯基特淋巴瘤的~12%，伯基特淋巴瘤的~9%， 弥漫性大B细胞淋巴瘤，高达36%的复发性弥漫性大B细胞淋巴瘤病例）携带复发性 FOXO 1是Forkhead转录因子Fox-O家族的成员。FOXO1 控制B细胞发育过程中的关键阶段转换，并且是PI 3 K/AKT途径的主要靶标， 它将关键的生存信号传递到B细胞受体的下游。当FOXO 1失活时， 淋巴瘤通常被认为是多种癌症类型和动物模型中的肿瘤抑制因子， 预测相关的FOXO 1突变反而会通过使FOXO 1的活性降低而将FOXO 1锁定在组成性活性状态， 它对PI 3 K依赖性核输出和降解不敏感。 在最近的一项研究中，我们发现FOXO 1对于维持特定的B细胞命运程序是至关重要的， 控制着地磁中心的纬向极性。一致地，FOXO 1空的遗传学中心不支持 一些关键的生物学功能通常与区域极性相关，包括亲和力成熟， 类别转换重组。该项目旨在了解淋巴瘤相关突变如何影响 FOXO 1在生发中心B细胞中的活性，以及这些事件如何可能有助于 生殖中心来源的B细胞非霍奇金淋巴瘤。我们认为FOXO 1突变积极地促进了 通过改变生发中心极性的控制和B细胞对特异性 免疫信号 为了验证这一观点，我们将开发以下具体目标：1）研究FOXO 1突变如何改变B细胞 应激激活蛋白激酶途径驱动的反应，结合体外和体内化学遗传学 在正常的癌性生发中心B细胞中测量和操纵FOXO 1对这些细胞的反应的策略 具体途径;通过分析原发性B-NHL病例进一步验证; 2）确定 FOXO 1突变通过基因工程改造生发中心B细胞对生发中心B细胞稳态的影响 用特定的错义突变，以评估它们对生发中心极性的影响， 3）评估FOXO 1突变在基因表达中的作用。 MYC驱动的B细胞淋巴瘤的发病机制，通过使用过继转移策略来模拟体内 MYC失调和FOXO 1突变共存的伯基特淋巴瘤的一部分（~12%）的遗传学。 考虑到FOXO 1在正常生殖中心生理学中的作用，本研究的结果有望提供 直接洞察到细胞和分子机制参与的发病机制，生发中心衍生 B细胞非霍奇金淋巴瘤。这些研究很可能是临床相关的，因为越来越多的 PI 3 K抑制剂作为这组恶性肿瘤的治疗剂的兴趣。