Role of IRF4-NOTCH2 Interplay in B-Cell Development and Malignancy

IRF4-NOTCH2 相互作用在 B 细胞发育和恶性肿瘤中的作用

• 批准号: 8625730
• 负责人: ULF KLEIN
• 金额: $ 16.88万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8625730
• 关键词: Antibodies; B lymphoid malignancy; B-Cell Acute Lymphoblastic Leukemia; B-Cell Development; B-Cell Neoplasm; B-Lymphocyte Subsets; B-Lymphocytes; Binding; Biological; Biological Assay; Cancer Etiology; Cell physiology; ChIP-seq; Chronic Lymphocytic Leukemia; Development; Disease; Equilibrium; Foundations; Gene Expression; Genes; Goals; Health; Homing; Interferon Regulatory Factor 4; Link; Lymphoid; Lymphoid Tissue; Lymphomagenesis; Malignant Neoplasms; Mature B-Lymphocyte; Mediating; Messenger RNA; MicroRNAs; Mission; Molecular; Multiple Myeloma; Mus; Mutation; Non-Hodgkin' s Lymphoma; Oncogenes; Oncogenic; Outcome; Pathogenesis; Pathway interactions; Phenotype; Positioning Attribute; Property; Proteins; Public Health; Publishing; Regulation; Research; Research Proposals; Role; Signal Transduction; Staging; Testing; Therapeutic; Therapeutic Intervention; Tumor Suppressor Proteins; Ubiquitination; United States National Institutes of Health; Up-Regulation; Work; base; cell motility; effective therapy; genome wide association study; genome-wide; human data; in vivo; innovation; large cell Diffuse non-Hodgkin' s lymphoma; migration; mouse model; neoplastic cell; programs; protein expression; trafficking; transcription factor; transcriptome sequencing; treatment strategy; tumor

DESCRIPTION (provided by applicant): This research proposal aims at elucidating the potential tumor-suppressor function of the transcription factor interferon regulatory factor 4 (IRF4) in B-cell malignancy. The development of B cells is tightly controlled by the coordinated expression of master transcriptional regulators. Aberrant expression of these regulators due to genetic alterations can disrupt ordered B-cell development and contribute to oncogenic transformation. Our long-term goal is to identify the roles of IRF4 in B-cell development, since deregulation of the biological programs controlled by IRF4 has been linked to the pathogenesis of several types of B-cell tumors. IRF4 can act as an oncogene in tumors of late B-cell stages, including multiple myeloma, whereas it has been identified as a potential tumor suppressor in chronic lymphocytic leukemia (CLL), a malignancy of quiescent mature B cells. Such opposing pathogenic roles of a single transcription factor imply the existence of fundamentally different biological programs controlled by IRF4 in different B-cell subsets. Thus, there is a need to elucidate the stage-specific function of IRF4 in order to understand its diverse pathogenic roles. While there is accumulating information on the function of IRF4 in the late stages of B-cell development, the role of IRF4 in quiescent mature B cells remains largely unexplored. Our goal here is to identify the role of IRF4 in mature B cells in order to understand the potential tumor-suppressor function of IRF4 in the pathogenesis of CLL. We have obtained preliminary evidence in a mouse model suggesting that IRF4-deficiency causes aberrant migration and homing of mature B cells, possibly due to hyperactivation of NOTCH2 signaling. The objective of the proposed work is to determine the molecular mechanisms by which IRF4 controls trafficking of mature B cells through regulation of NOTCH2 activation in order to understand the biological consequences of IRF4 deficiency in B-cell malignancy. Our central hypothesis is that alterations in the balance of the transcriptional network established by IRF4 and NOTCH2 may disrupt the normal migration and homing properties of B cells and thereby contribute to lymphomagenesis by aberrantly positioning transformed B cells in a lymphoid microenvironment that supports survival. To accomplish the objective of this application, we will elucidate the molecular mechanism by which IRF4 regulates NOTCH2 activation. In addition, we will determine the biological program controlled by NOTCH2 in IRF4-deficient B cells by performing a genome-wide identification of transcriptional targets. We will also identify the role of the IRF4-NOTCH2 interplay in cell migration in vivo by exploring the consequences of NOTCH2-inhibition in IRF4-deficient B cells, using a therapeutically active NOTCH2-inhibitory antibody. The rationale for the proposed research is that elucidating the functional interplay between IRF4 and NOTCH2 in normal B-cell physiology and its disruption in malignancy has the potential to provide the basis for developing innovative therapeutic strategies targeted at CLL and other B-cell tumors where NOTCH2 hyperactivation has been associated with tumor-promoting roles.

描述（由申请人提供）：本研究计划旨在阐明转录因子干扰素调节因子4 （IRF4）在b细胞恶性肿瘤中的潜在肿瘤抑制功能。B细胞的发育受到主转录调控因子的协调表达的严格控制。由于基因改变，这些调节因子的异常表达可以破坏有序的b细胞发育并促进致癌转化。我们的长期目标是确定IRF4在b细胞发育中的作用，因为IRF4控制的生物学程序的解除与几种类型b细胞肿瘤的发病机制有关。IRF4可以作为晚期B细胞肿瘤的致癌基因，包括多发性骨髓瘤，而它已被确定为慢性淋巴细胞白血病（CLL）的潜在肿瘤抑制因子，CLL是一种静止成熟B细胞的恶性肿瘤。单个转录因子的这种相反的致病作用表明，在不同的b细胞亚群中存在由IRF4控制的根本不同的生物学程序。因此，有必要阐明IRF4的分期特异性功能，以了解其不同的致病作用。虽然关于IRF4在B细胞发育后期的功能的信息越来越多，但IRF4在静止成熟B细胞中的作用仍然很大程度上未被探索。我们的目标是确定IRF4在成熟B细胞中的作用，以了解IRF4在CLL发病机制中的潜在肿瘤抑制功能。我们在小鼠模型中获得了初步证据，表明irf4缺陷导致成熟B细胞的异常迁移和归巢，可能是由于NOTCH2信号的过度激活。这项工作的目的是确定IRF4通过调节NOTCH2激活来控制成熟B细胞运输的分子机制，以了解IRF4缺乏在B细胞恶性肿瘤中的生物学后果。我们的中心假设是，IRF4和NOTCH2建立的转录网络平衡的改变可能会破坏B细胞的正常迁移和归巢特性，从而通过在支持生存的淋巴样微环境中异常定位转化的B细胞来促进淋巴瘤的发生。为了实现这一应用的目标，我们将阐明IRF4调节NOTCH2激活的分子机制。此外，我们将通过对转录靶点进行全基因组鉴定，确定irf4缺陷B细胞中NOTCH2控制的生物学程序。我们还将使用具有治疗活性的notch2抑制抗体，通过探索irf4缺陷B细胞中notch2抑制的后果，确定IRF4-NOTCH2相互作用在细胞迁移中的作用。该研究的基本原理是阐明IRF4和NOTCH2在正常b细胞生理及其在恶性肿瘤中的破坏之间的功能相互作用，有可能为开发针对CLL和其他NOTCH2过度激活与肿瘤促进作用相关的b细胞肿瘤的创新治疗策略提供基础。

项目成果

IRF4 controls the positioning of mature B cells in the lymphoid microenvironments by regulating NOTCH2 expression and activity.

• DOI: 10.1084/jem.20131026
• 发表时间: 2013-12-16
• 期刊: The Journal of experimental medicine
• 作者: Simonetti G;Carette A;Silva K;Wang H;De Silva NS;Heise N;Siebel CW;Shlomchik MJ;Klein U
• 通讯作者: Klein U