Proteomic biomarkers of ALK+ lymphoma

ALK 淋巴瘤的蛋白质组生物标志物

• 批准号: 8196784
• 负责人: Megan S. Lim
• 金额: $ 31.1万
• 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: 2009-12-03 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8196784
• 关键词: Behavior Therapy; Bioinformatics; Biological Assay; Biological Markers; Biology; Cations; Cell Adhesion; Cell Line; Cell Survival; Cells; Characteristics; Child; Childhood; Childhood Non-Hodgkin' s Lymphoma; Children' s Oncology Group; Chromosomal translocation; Chromosome abnormality; Clinical; Complication; DNA Damage; Data Analyses; Detection; Diagnosis; Diagnostic; Disease; Disease-Free Survival; Early Diagnosis; Event; Genetic; Goals; Healthcare; Human; Immunohistochemistry; In Vitro; Investigation; Ki-1 Large-Cell Lymphoma; Label; Lead; Lymphoid Cell; Lymphoma; Lymphomagenesis; Malignant Neoplasms; Malignant lymphoid neoplasm; Mass Spectrum Analysis; Mediating; Mediator of activation protein; Methods; Modeling; Molecular; Molecular Biology; Non-Hodgkin' s Lymphoma; Oncogenes; Outcome; Pathogenesis; Pathway Analysis; Pathway interactions; Patient Monitoring; Patients; Peptides; Peripheral; Phosphoproteins; Phosphorylation; Play; Primary Neoplasm; Protein Tyrosine Kinase; Proteins; Proteomics; RNA Interference; Receptor Protein-Tyrosine Kinases; Refractory; Relapse; Research; Sampling; Screening for cancer; Signal Pathway; Signal Transduction; Stable Isotope Labeling; Staging; T-Cell Lymphoma; Therapeutic; Tissue Sample; Tyrosine; Validation; Western Blotting; advanced disease; anaplastic lymphoma kinase; base; cell motility; cohort; in vivo; multicatalytic endopeptidase complex; novel; nucleophosmin; outcome forecast; overexpression; prognostic; public health relevance; t(2; 5)(p23; q35); tumor; tumorigenesis; validation studies; vector; working group

DESCRIPTION (provided by applicant): Anaplastic large-cell lymphoma (ALCL) is a distinct subtype of peripheral T-cell lymphomas harboring chromosomal translocations involving the ALK tyrosine kinase. ALCL represents about 10% of all childhood non-Hodgkin lymphoma (NHL). The t(2;5)(p23;q35) chromosomal aberration resulting in overexpression of a chimeric oncogene, nucleophosmin-anaplastic lymphoma kinase (NPM/ALK) is the most common translocation found in these tumors. The NPM/ALK protein plays a key role in ALCL lymphomagenesis and has been shown to cause lymphoid malignancy in vitro and in vivo. Although, the prognosis of localized childhood ALCL is excellent with 5 year survival ranging from 90-95%, children with advanced stage ALCL only have a 5 year survival of about 60% with late relapses are a common complication. Since 70% of children present with advanced disease, 25%-35% of all children with ALCL will relapse or become refractory to initial treatment. Biomarkers of ALCL that can be useful for diagnosis, early detection, prediction of biologic behavior and therapy are needed. Novel targeted therapies are needed for children with refractory/relapsed ALCL and for the subset of children with a poor prognosis at diagnosis. 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 NPM/ALK-positive lymphomas. In specific aim 1, we will perform global quantitative proteomic analysis in an unbiased manner to identify the proteomic and phosphoproteomic changes associated with the expression of NPM/ALK in human lymphoid cells. In specific aim 2, we will establish the functional relevance of selected components of the MS-derived NPM/ALK signaling pathways. Our long-term goal is to identify robust, sensitive and specific protein biomarkers for the detection of NPM/ALK-positive ALCLs. Our studies have implications for the identification of disease biomarkers for other forms of cancers characterized by ALK deregulation. PUBLIC HEALTH RELEVANCE: Health-care impact. Children with advanced stage ALCL only have a 5 year event free survival of about 60% with late relapses as a common complication. Since 70% of children present with advanced disease, 25%-35% of all children with ALCL will relapse or become refractory to initial treatment. Biomarkers of ALCL that can be useful for diagnosis, early detection, prediction of biologic behavior and therapy are needed. In addition, novel targeted therapies are needed for children with refractory/relapsed ALCL and for the subset of children with a poor prognosis at diagnosis. 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 NPM/ALK-positive lymphomas. Our proposed studies offer an opportunity for the discovery of robust, sensitive biomarkers of ALCL. Collectively, our studies will lead to identification of protein biomarkers of NPM/ALK lymphomas that will be important for the diagnostic assessment, treatment and monitoring of patients with ALCL.

描述（由申请人提供）：肿瘤大细胞淋巴瘤（ALCL）是携带涉及碱酪氨酸激酶的染色体易位的周围T细胞淋巴瘤的独特亚型。 ALCL约占所有儿童非霍奇金淋巴瘤（NHL）的10％。 t（2; 5）（p23; q35）染色体像差导致过度表达嵌合癌基因，核磷酸化症 - 磷酸 - 磷酸淋巴瘤激酶（NPM/ALK）是在这些肿瘤中发现的最常见的易位。 NPM/ALK蛋白在ALCL淋巴作用中起关键作用，并且已被证明会在体外和体内引起淋巴性恶性肿瘤。尽管局部儿童ALCL的预后非常出色，5年生存率为90-95％，但患有晚期ALCL的儿童仅有5年生存率约为60％，而晚期复发是常见的并发症。由于有70％的患有晚期疾病的儿童，所有ALCL儿童中有25％-35％会复发或对初始治疗难治性。 ALCL的生物标志物需要用于诊断，早期检测，生物行为和治疗的预测。难治性/复发性ALCL的儿童需要新的靶向疗法，以及预后不良的儿童子集。在此应用中，我们建议利用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NPM/ALK阳性淋巴瘤的蛋白质组学生物标志物。在特定目标1中，我们将以公正的方式进行全局定量蛋白质组学分析，以识别与人淋巴细胞中NPM/ALK表达相关的蛋白质组学和磷酸蛋白质组学变化。在特定的目标2中，我们将建立MS衍生的NPM/ALK信号通路的选定组件的功能相关性。我们的长期目标是确定可检测NPM/ALK阳性ALCLS的强大，敏感和特定的蛋白质生物标志物。我们的研究对以ALK放松管制为特征的其他形式的癌症鉴定疾病生物标志物具有影响。 公共卫生相关性：医疗保健影响。 ADAD ALCL晚期的儿童只有5年的免费生存率约为60％，而后期复发是常见的并发症。由于有70％的患有晚期疾病的儿童，所有ALCL儿童中有25％-35％会复发或对初始治疗难治性。 ALCL的生物标志物需要用于诊断，早期检测，生物行为和治疗的预测。此外，对于难治性/复发性ALCL的儿童以及诊断前预后不良的儿童子集需要新颖的靶向疗法。在此应用中，我们建议利用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NPM/ALK阳性淋巴瘤的蛋白质组学生物标志物。我们提出的研究为发现ALCL的强大，敏感的生物标志物提供了机会。总体而言，我们的研究将导致鉴定NPM/ALK淋巴瘤的蛋白质生物标志物，这对于ALCL患者的诊断评估，治疗和监测至关重要。