Role of FOXP1 and WNT signaling in B-cell Lymphoma

 描述(申请人提供)：Wnt/β-catenin信号通路是一种进化保守的受体介导的信号转导通路，在发育、再生和疾病中控制细胞的增殖和分化。在许多上皮性癌症中，核心信号元件的突变激活了Wnt/β-catenin。同样，在包括套细胞淋巴瘤和弥漫性大B细胞淋巴瘤(DLBCL)在内的各种血液系统恶性肿瘤中也观察到异常的通路活性。然而，与癌症不同的是，这些非上皮性癌症中的大多数缺乏核心WNT/？-catenin核心成分的突变，这使得通路激活的分子基础尚不清楚。利用一种新的基于质谱学的功能增益筛选方法，我们发现Foxp1转录因子激活了WNT/？-catenin信号。Foxp1在发育和疾病过程中指导细胞分化；它控制胚胎干细胞的多能性，并指导B细胞、角质形成细胞、神经元、心脏和肺细胞的分化。在癌症中，Foxp1在B细胞淋巴瘤中表现出致癌特征，最明显的是在套细胞淋巴瘤和DLBCL中，拷贝数扩增和染色体易位导致其高表达。Foxp1在DLBCL中的过度表达预示着患者预后不良，是治疗抵抗的主要标志。尽管Foxp1在DLBCL中具有疾病和发育的重要性，但其下游效应因子尚不清楚。同样，尽管WNT/？连环蛋白信号在许多上皮性癌症中存在明显的作用，但WNT/？连环蛋白信号在DLBCL中的作用如何以及在多大程度上仍不清楚。我们假设，Foxp1的过表达通过增强Wnt/？-catenin信号通路促进淋巴癌的发生。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，Foxp1的表达通过CBP乙酰转移酶诱导？连环蛋白乙酰化，导致？连环蛋白依赖的转录。第二，我们发现Foxp1控制DLBCL对WNT/？-catenin小分子抑制剂的敏感性。第三，我们发现在小鼠异种移植模型中，Foxp1和Wnt/？catenin促进了DLBCL肿瘤的生长。在这项建议中，我们描述了一项研究计划，以探索Foxp1和Wnt/ü-catenin途径影响DLBCL生长和存活的机制(S)和生理相关性。我们将进一步完善我们的WNT/？连环蛋白激活模型，特别关注DLBCL肿瘤中Foxp1的选择性剪接和？连环蛋白的转录活性。将使用细胞模型和小鼠肿瘤移植模型来评估Foxp1和WNT/？-catenin信号在DLBCL中的表型影响，包括WNT/？-catenin抑制剂的疗效研究。我们建议的研究旨在确定在特定的B细胞淋巴瘤人群中，Foxp1的过表达促进WNT/？-catenin信号转导，从而为WNT导向的B细胞淋巴瘤治疗提供分子基础。

 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/ß-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/ß-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/ß-catenin signaling contributes to DLBCL is unclear. We hypothesize that FOXP1 overexpression promotes lymphomagenesis through potentiation of the WNT/ß-catenin signaling pathway. Our preliminary data support this model. First, proteomic and genetic study revealed that FOXP1 expression induced ß-catenin acetylation by the CBP acetyl transferases, resulting in ß-catenin-dependent transcription. Second, we found that FOXP1 controls the sensitivity of DLBCL to WNT/ß-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/ß-catenin pathway affect DLBCL growth and survival. We will further refine our model of WNT/ß-catenin activation, with specific attention to FOXP1 alternative splicing and ß-catenin transcriptional activity in DLBCL tumors. Cell models and mouse tumor xenografts will be used to phenotypically assess the impact of FOXP1 and WNT/ß-catenin signaling in DLBCL, including efficacy studies of WNT/ß-catenin inhibitors. Our proposed studies aim to establish that FOXP1 overexpression promotes WNT/ß-catenin signaling in specific populations of B-cell lymphoma, thus providing a molecular rationale for WNT-directed therapies in B-cell lymphoma.