Proteomic analysis of api2-MALT1 positive gastric MALT lymphoma

api2-MALT1阳性胃MALT淋巴瘤的蛋白质组学分析

• 批准号: 8035900
• 负责人: KOJO S. J. ELENITOBA-JOHNSON
• 金额: $ 27.87万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-26 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8035900
• 关键词: Affect; Aggressive Clinical Course; Anatomic Sites; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Antigens; Behavior Therapy; Bioinformatics; Biological Markers; Biopsy Specimen; Cells; Characteristics; Chimeric Proteins; Chromosomal translocation; Chromosome abnormality; Communities; Data; Dependence; Detection; Diagnosis; Diagnostic; Disease; Disease Association; Early Diagnosis; Event; Extranodal; Gastric Juice; Gastric lymphoma; Gastric mucosa; Generations; Goals; Health; Helicobacter Infections; Helicobacter pylori; Human; Immunohistochemistry; Incidence; Indium; Infection; Interest Group; Ions; Isotopes; Knowledge; Light; Lymphoid Cell; Lymphoma; Lymphomagenesis; Malignant Neoplasms; Mass Spectrum Analysis; Molecular Profiling; Monitor; NIH Program Announcements; Neoplasms; Non-Hodgkin' s Lymphoma; Oncogenic; Organism; Pathogenesis; Pathway interactions; Patients; Peptides; Plasma; Proteins; Proteomics; Reaction; Recurrence; Resistance; Risk; Sampling; Series; Site; Stomach; Therapeutic; Treatment Protocols; Trypsin; Validation; Western Blotting; antimicrobial; base; computerized tools; human tissue; minimally invasive; mucosa-associated lymphoid tissue; mucosa-associated lymphoid tissue lymphoma; outcome forecast; response; t(11; 18)(q21; q21); tandem mass spectrometry; therapeutic target; treatment strategy; tumor

DESCRIPTION (provided by applicant): Extranodal marginal zone lymphomas of mucosa associated lymphoid tissue are one of the most common forms of non-Hodgkin lymphoma with steadily increasing incidence over the last two decades. The most common site of involvement is the stomach. Extranodal marginal zone lymphomas of the stomach (gastric MALT lymphomas) are associated with infection by the Helicobacter pylori organism in the vast majority of cases. The recognition of strong association of this disease with H. pylori and the dependence of the vast majority of the tumors on H. pylori antigen supported the revolutionary introduction of antibiotic regimens for the treatment of this form of cancer. In this regard, antibiotic eradication of the organism leads to regression of the gastric MALT lymphomas in up to 75% of cases. However, a subset of cases acquire a recurrent chromosomal translocation the t(11;18) which leads to the generation of an abnormal protein, the api2/MALT1 fusion that is important in the pathogenesis of this neoplasm. Importantly, api2/MALT1-positive lymphomas are unresponsive to antibiotic therapy and are characterized by a more aggressive clinical course. Currently, there are no known proteomic biomarkers for this antibiotic resistant form of gastric MALT lymphoma. Accordingly, in this application, we propose to utilize a suite of quantitative mass spectrometry-based proteomics strategies supported by sophisticated bioinformatics approaches to identify proteomic biomarkers of api2/MALT1 expressing MALT lymphomas. In specific aim 1, we will perform global quantitative proteomic analysis in an unbiased fashion to identify the proteomic changes associated with expression of the api2/MALT1 fusion in mature human lymphoid cells. In specific aim 2, we will develop a series of highly selective ion reaction monitoring strategies to detect api2/MALT1-positive lymphomas. In specific aim 3, we will investigate the utility of the api2/MALT1 specific biomarkers for the detection of api2/MALT1 lymphomas in biopsy specimens, gastric juice and in plasma/serum samples. In specific aim 4, we will make accessible and disseminate our raw and tandem mass spectrometry data for unrestricted interrogation by other groups. Our long-term goal is to identify robust, sensitive and specific biomarkers for the detection of the antibiotic-resistant api2/MALT1-positive form of extranodal marginal zone lymphoma. These studies have broad implications for the potential of quantitative mass spectrometry-based approaches for the identification of disease biomarkers for all forms of cancer. PUBLIC HEALTH RELEVANCE: The most common site affected by extranodal marginal zone B-cell lymphomas of mucosa associated lymphoid tissue is the stomach. This form of non-Hodgkin lymphoma is strongly and causally associated with the presence of a bacterial organism, Helicobacter pylori. In the majority of cases, antibiotic and antimicrobial therapy targeting the organism is an effective strategy for the treatment of this form of cancer. However, a subset of these gastric MALT lymphomas does not respond to antibiotic therapy and pursue an aggressive clinical course with adverse prognosis. The vast majority of these antibiotic resistant cases have been shown to harbor a chromosomal aberration which leads to the expression of an abnormal fusion protein known as api2-MALT1. There are no well-developed proteomic biomarkers for detection of this antibiotic resistant form of MALT lymphoma. Using sophisticated mass spectrometry strategies, we will identify the proteomic biomarkers of api2-MALT1-positive lymphomas. Our studies offer an opportunity for the early detection of antibiotic resistant gastric MALT lymphoma. The ability to routinely detect api2-MALT1-positive lymphoma with a minimally invasive approaches is a critical element in the overall strategy for the effective management and therapeutic monitoring of antibiotic resistant gastric MALT lymphoma.

描述（由申请人提供）：粘膜相关淋巴组织的乳形外边缘区淋巴瘤是非霍奇金淋巴瘤最常见的形式之一，在过去的二十年中稳步增加。最常见的参与部位是胃。在绝大多数病例中，胃的胃淋巴结（胃麦芽淋巴瘤）与幽门螺杆菌的感染有关。这种疾病与幽门螺杆菌的强烈关联以及绝大多数肿瘤对幽门螺杆菌抗原的依赖性支持了革命性的抗生素方案，以治疗这种形式的癌症。在这方面，消除生物体的抗生素导致胃麦芽淋巴瘤在多达75％的病例中消退。然而，一部分病例获得了复发性染色体易位的T（11; 18），导致异常蛋白的产生，API2/MALT1融合在该肿瘤的发病机理中很重要。重要的是，API2/MALT1阳性淋巴瘤对抗生素疗法无反应，其特征是更具侵略性的临床过程。当前，这种抗生素抗生素形式的胃麦芽淋巴瘤尚无已知的蛋白质组学生物标志物。因此，在本应用中，我们建议利用一套由复杂的生物信息学方法支持的基于定量质谱的蛋白质组学策略，以鉴定表达麦芽淋巴瘤的API2/MALT1的蛋白质组学生物标志物。在特定的目标1中，我们将以公正的方式进行全局定量蛋白质组学分析，以识别与成熟的人淋巴样细胞中API2/MALT1融合表达相关的蛋白质组学变化。在特定目标2中，我们将开发一系列高度选择性的离子反应监测策略，以检测API2/MALT1阳性淋巴瘤。在特定目标3中，我们将研究API2/MALT1特异性生物标志物在活检标本，胃汁和血浆/血清样品中检测API2/MALT1淋巴瘤的效用。在特定的目标4中，我们将使我们的原始和串联质谱数据可访问并传播其他群体无限制的询问。我们的长期目标是确定可检测抗生素抗生素的API2/MALT1阳性形式的强大，敏感和特定的生物标志物。这些研究对基于定量质谱的方法的潜力具有广泛的影响，以鉴定所有形式的癌症疾病生物标志物。 公共卫生相关性：受粘膜相关淋巴组织的最常见的部位B细胞淋巴瘤影响的最常见部位是胃。这种非霍奇金淋巴瘤的这种形式与细菌生物幽门螺杆菌的存在密切和因果关系。在大多数情况下，针对生物体的抗生素和抗菌治疗是治疗这种形式癌症的有效策略。但是，这些胃麦芽淋巴瘤的一部分对抗生素疗法没有反应，并采用不良预后的积极临床过程。这些抗生素耐药性病例中的绝大多数已显示出具有染色体畸变，从而导致异常融合蛋白的表达称为API2-MALT1。没有发达的蛋白质组学生物标志物来检测这种抗生素淋巴瘤的抗生素形式。使用复杂的质谱策略，我们将确定API2-MALT1阳性淋巴瘤的蛋白质组学生物标志物。我们的研究为早期检测抗生素抗生素胃麦芽淋巴瘤提供了机会。常规检测使用微创方法的API2-MALT1阳性淋巴瘤的能力是有效管理和治疗性抗生素耐药性胃麦芽淋巴瘤的总体策略的关键要素。