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

基本信息

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
项目类别：
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&apos s lymphoma member mutant novel novel therapeutic intervention programs response stress activated protein kinase transcription factor

项目摘要

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.

项目概要/摘要部分生发中心来源的 B 细胞非霍奇金淋巴瘤（约 12% 的伯基特淋巴瘤，约 9% 的伯基特淋巴瘤）弥漫性大 B 细胞淋巴瘤，高达 36% 的复发性弥漫性大 B 细胞淋巴瘤病例会复发 FOXO1（叉头转录因子 Fox-O 家族的成员）发生错义突变。 FOXO1 控制 B 细胞发育过程中的关键阶段转变，是 PI3K/AKT 通路的主要靶标，它在 B 细胞受体下游传递关键的生存信号。虽然 FOXO1 已失活，因此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计相关的 FOXO1 突变会通过使 FOXO1 锁定在组成型活性状态它对 PI3K 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 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带状极性。一致地，FOXO1 无效生发中心无法支持一些通常与带状极性相关的关键生物功能，包括亲和力成熟和类别转换重组。该项目旨在了解淋巴瘤相关突变如何影响 FOXO1 在生发中心 B 细胞中的活性，以及这些事件如何影响 B 细胞的发病机制生发中心来源的 B 细胞非霍奇金淋巴瘤。我们认为 FOXO1 突变积极贡献通过改变生发中心极性的控制和 B 细胞对特定的反应来影响 B 细胞淋巴瘤发生免疫信号。为了检验这个想法，我们将制定以下具体目标：1) 研究 FOXO1 突变如何改变 B 细胞由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正常癌性生发中心 B 细胞测量和操纵 FOXO1 对这些细胞的反应的策略具体途径；通过对原发性 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 细胞稳态的影响具有特定的错义突变，以评估其对生发中心极性和控制的影响生发中心特异性 FOXO1 转录程序； 3) 评估FOXO1突变在通过使用过继转移策略来模拟体内 MYC 驱动的 B 细胞淋巴瘤的发病机制部分伯基特淋巴瘤 (~12%) 的遗传学，其中 MYC 失调和 FOXO1 突变共存。鉴于 FOXO1 在正常生发中心生理学中的作用，本研究的结果有望提供直接洞察生发中心来源的发病机制所涉及的细胞和分子机制 B 细胞非霍奇金淋巴瘤。由于日益增长的研究，这些研究可能具有临床相关性人们对 PI3K 抑制剂作为这类恶性肿瘤的治疗剂感兴趣。