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Role of FOXP1 and WNT signaling in B-cell Lymphoma

FOXP1 和 WNT 信号在 B 细胞淋巴瘤中的作用

基本信息

批准号：
10025735
负责人：
Michael Benjamin Major
金额：
$ 29.83万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-04 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10025735
关键词：
Acetylation Acylation Adult Affect Alternative Splicing Attention B-Cell Lymphomas B-Lymphocytes Binding Biochemical Biological Assay Biological Markers Biopsy Carcinoma Cardiac Cell Differentiation process Cell Fate Control Cell Line Cell Proliferation Cell model Cells ChIP-seq Characteristics Chemosensitization Chromatin Chromosomal translocation Clinical Clinical Trials Colon Carcinoma Complex Coupled Data Development Disease Enzymes Etiology FOXP1 gene Gene Expression Gene Expression Profiling Genes Genetic Screening Genetic Transcription Genetic study Genome Growth Hematologic Neoplasms Homeostasis Human In Vitro Lead Ligands Lung Lymphoma Lymphomagenesis Malignant Neoplasms Malignant neoplasm of liver Mammary Neoplasms Mantle Cell Lymphoma Mass Spectrum Analysis Modality Modeling Molecular Molecular Biology Mus Mutation Natural regeneration Neurons Oncogenic Pathway interactions Patients Pharmacology Phase Phenotype Physiological Population Protein Isoforms Protein Overexpression Proteins Proteomics Publishing RNA Splicing Receptor Mediated Signal Transduction Regulation Research Role Signal Pathway Signal Transduction Signal Transduction Pathway TCF7L2 gene Testing Tissues Transcriptional Activation Transferase Variant WNT Signaling Pathway Xenograft Model activating transcription factor base beta catenin comparative design efficacy study embryonic stem cell experimental study gain of function genetic signature improved inhibitor/antagonist insight keratinocyte large cell Diffuse non-Hodgkin&apos s lymphoma loss of function novel outcome forecast outcome prediction overexpression patient stratification pluripotency pre-clinical promoter public health relevance response screening small molecule inhibitor therapeutic biomarker therapy resistant transcription factor tumor tumor growth tumor xenograft tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The Wnt/β-catenin signaling pathway is an evolutionarily conserved receptor-mediated signal transduction pathway that controls cell proliferation and differentiation during development, regeneration and in disease. Mutation of core signaling components activates Wnt/β-catenin in many epithelial cancers. Likewise, aberrant pathway activity has been observed in various hematological malignancies, including mantle cell lymphoma and diffuse large B-cell lymphoma (DLBCL). However, unlike carcinoma, the majority of these non-epithelial cancers lack telltale mutations in core WNT/β-catenin components, leaving the molecular underpinnings of pathway activation unclear. Using a new mass spectrometry-based gain-of-function screening approach, we discovered that the FOXP1 transcription factor activates WNT/β-catenin signaling. FOXP1 directs cell differentiation during development and disease; it controls embryonic stem cell pluripotency and instructs B-cell, keratinocyte, neuronal, cardiac and lung cell differentiation. In cancer, FOXP1 demonstrates oncogenic characteristics in B-cell lymphoma, most notably in mantle cell lymphoma and DLBCL where copy number amplifications and chromosomal translocations contribute to its high expression. FOXP1 overexpression in DLBCL predicts poor patient prognosis and is a leading marker therapeutic resistance. Despite its disease and developmental importance, the downstream effectors of FOXP1 in DLBCL are not known. Likewise, although a clear role for WNT/ß- catenin signaling exists in many epithelial cancers, how and to what extent WNT/β-catenin signaling contributes to DLBCL is unclear. We hypothesize that FOXP1 overexpression promotes lymphomagenesis through potentiation of the WNT/β-catenin signaling pathway. Our preliminary data support this model. First, proteomic and genetic study revealed that FOXP1 expression induced β-catenin acetylation by the CBP acetyl transferases, resulting in β-catenin-dependent transcription. Second, we found that FOXP1 controls the sensitivity of DLBCL to WNT/β-catenin small molecule inhibitors. Third, we discovered that FOXP1 and WNT/ß-catenin promote DLBCL tumor growth in a mouse xenograft model. In this proposal, we describe a research plan to explore the mechanism(s) and physiological relevance by which FOXP1 and the WNT/β-catenin pathway affect DLBCL growth and survival. We will further refine our model of WNT/β-catenin activation, with specific attention to FOXP1 alternative splicing and β-catenin transcriptional activity in DLBCL tumors. Cell models and mouse tumor xenografts will be used to phenotypically assess the impact of FOXP1 and WNT/β-catenin signaling in DLBCL, including efficacy studies of WNT/ß-catenin inhibitors. Our proposed studies aim to establish that FOXP1 overexpression promotes WNT/β-catenin signaling in specific populations of B-cell lymphoma, thus providing a molecular rationale for WNT-directed therapies in B-cell lymphoma.

描述（由申请人提供）：Wnt/β-连环蛋白信号通路是一种进化上保守的受体介导的信号转导通路，在发育、再生和疾病期间控制细胞增殖和分化。在许多上皮癌中，核心信号传导组分的突变激活Wnt/β-连环蛋白。同样，在各种血液恶性肿瘤中观察到异常途径活性，包括套细胞淋巴瘤和弥漫性大B细胞淋巴瘤（DLBCL）。然而，与癌症不同，大多数这些非上皮性癌症在核心WNT/β-连环蛋白组分中缺乏指示性突变，使得通路激活的分子基础不清楚。使用一种新的基于质谱的功能获得筛选方法，我们发现FOXP 1转录因子激活WNT/β-catenin信号传导。FOXP 1在发育和疾病期间指导细胞分化;它控制胚胎干细胞多能性并指导B细胞、角质形成细胞、神经元、心脏和肺细胞分化。在癌症中，FOXP 1在B细胞淋巴瘤中表现出致癌特征，最显著的是在套细胞淋巴瘤和DLBCL中，其中拷贝数扩增和染色体易位有助于其高表达。DLBCL中FOXP 1过表达预示患者预后不良，是治疗耐药的主要标志物。尽管FOXP 1在疾病和发育中具有重要意义，但其在DLBCL中的下游效应子尚不清楚。同样，尽管WNT/β-连环蛋白信号传导在许多上皮癌中存在明确的作用，但WNT/β-连环蛋白信号传导如何以及在多大程度上促成DLBCL尚不清楚。我们推测FOXP 1过表达通过增强WNT/β-catenin信号通路促进淋巴瘤发生。我们的初步数据支持这一模型。首先，蛋白质组学和遗传学研究表明，FOXP 1的表达通过CBP乙酰转移酶诱导β-catenin乙酰化，导致β-catenin依赖性转录。其次，我们发现FOXP 1控制DLBCL对WNT/β-catenin小分子抑制剂的敏感性。第三，我们发现FOXP 1和WNT/β-连环蛋白在小鼠异种移植模型中促进DLBCL肿瘤生长。在这个提议中，我们描述了一个研究计划，以探索FOXP 1和WNT/β-catenin通路影响DLBCL生长和存活的机制和生理相关性。我们将进一步完善我们的WNT/β-catenin激活模型，特别关注DLBCL肿瘤中FOXP 1选择性剪接和β-catenin转录活性。细胞模型和小鼠肿瘤异种移植物将用于表型评估F0 XP 1和WNT/β-连环蛋白信号传导在DLBCL中的影响，包括WNT/β-连环蛋白抑制剂的功效研究。我们提出的研究旨在确定FOXP 1过表达促进特定B细胞淋巴瘤群体中的WNT/β-catenin信号传导，从而为B细胞淋巴瘤中的WNT导向疗法提供分子基础。