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: 7565662
• 负责人: KOJO S. J. ELENITOBA-JOHNSON
• 金额: $ 28.92万
• 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/7565662
• 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; Figs - dietary; Gastric Juice; Gastric lymphoma; Gastric mucosa; Generations; Goals; 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; public health relevance; response; 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（由申请方提供）：粘膜相关淋巴组织的结外边缘区淋巴瘤是非霍奇金淋巴瘤最常见的形式之一，在过去二十年中发病率稳步上升。最常见的受累部位是胃。胃结外边缘区淋巴瘤（胃MALT淋巴瘤）在绝大多数病例中与幽门螺杆菌感染有关。认识到该病与H. pylori感染和绝大多数肿瘤对H.幽门螺杆菌抗原的发现支持了抗生素疗法的革命性引入，用于治疗这种形式的癌症。在这方面，抗生素根除微生物导致高达75%的胃MALT淋巴瘤消退。然而，一个子集的情况下获得一个复发性染色体易位的t（11;18），导致异常蛋白质的产生，api 2/MALT 1融合，这是重要的发病机制，这种肿瘤。重要的是，api 2/MALT 1阳性淋巴瘤对抗生素治疗无反应，其特征在于更具侵袭性的临床病程。目前，对于这种抗生素耐药形式的胃MALT淋巴瘤，还没有已知的蛋白质组学生物标志物。因此，在本申请中，我们提出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来鉴定表达MALT淋巴瘤的api 2/MALT 1的蛋白质组学生物标志物。在具体目标1中，我们将以无偏的方式进行全局定量蛋白质组学分析，以鉴定与成熟人淋巴细胞中api 2/MALT 1融合表达相关的蛋白质组学变化。在具体目标2中，我们将开发一系列高选择性离子反应监测策略来检测api 2/MALT 1阳性淋巴瘤。在具体目标3中，我们将研究api 2/MALT 1特异性生物标志物用于检测活检标本、胃液和血浆/血清样品中的api 2/MALT 1淋巴瘤的效用。在具体目标4中，我们将提供和传播我们的原始和串联质谱数据，供其他团体进行不受限制的询问。我们的长期目标是确定稳健，敏感和特异的生物标志物，用于检测结边缘区淋巴瘤的耐药api 2/MALT 1阳性形式。这些研究对基于定量质谱的方法用于鉴定所有形式癌症的疾病生物标志物的潜力具有广泛的意义。 公共卫生相关性：最常见的受粘膜相关淋巴组织结边缘区B细胞淋巴瘤影响的部位是胃。这种形式的非霍奇金淋巴瘤与细菌有机体幽门螺杆菌的存在密切相关。在大多数情况下，针对生物体的抗生素和抗微生物治疗是治疗这种癌症的有效策略。然而，这些胃MALT淋巴瘤的一个子集不响应抗生素治疗，并追求积极的临床过程与不良预后。这些抗生素耐药病例中的绝大多数已被证明具有染色体畸变，其导致称为api 2-MALT 1的异常融合蛋白的表达。目前还没有成熟的蛋白质组学生物标志物用于检测MALT淋巴瘤的这种抗生素耐药形式。使用复杂的质谱分析策略，我们将确定api 2-MALT 1阳性淋巴瘤的蛋白质组生物标志物。我们的研究为早期发现抗生素耐药的胃MALT淋巴瘤提供了机会。采用微创方法常规检测api 2-MALT 1阳性淋巴瘤的能力是抗生素耐药胃MALT淋巴瘤有效管理和治疗监测总体策略的关键要素。