Proteomic biomarkers of ALK+ lymphoma

ALK 淋巴瘤的蛋白质组生物标志物

• 批准号: 8385569
• 负责人: Megan S. Lim
• 金额: $ 29.23万
• 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/8385569
• 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.

描述（由申请方提供）：间变性大细胞淋巴瘤（ALCL）是外周T细胞淋巴瘤的一种独特亚型，具有涉及ALK酪氨酸激酶的染色体易位。ALCL占所有儿童非霍奇金淋巴瘤（NHL）的约10%。t（2; 5）（p23; q35）染色体畸变导致嵌合癌基因过表达，核磷蛋白-间变性淋巴瘤激酶（NPM/ALK）是这些肿瘤中最常见的易位。NPM/ALK蛋白在ALCL淋巴瘤发生中起关键作用，并已显示在体外和体内引起淋巴恶性肿瘤。虽然局部儿童ALCL的预后良好，5年生存率为90- 95%，但晚期ALCL儿童的5年生存率仅为60%左右，晚期复发是常见的并发症。由于70%的儿童患有晚期疾病，因此所有ALCL儿童中有25%-35%会复发或对初始治疗难治。因此，需要寻找对ALCL的诊断、早期发现、生物学行为预测和治疗有用的生物标志物。难治性/复发性ALCL儿童和诊断时预后不良的儿童亚组需要新型靶向治疗。在本申请中，我们建议利用一套基于定量质谱的蛋白质组学策略，由复杂的生物信息学方法支持，以确定NPM/ALK阳性淋巴瘤的蛋白质组学生物标志物。在具体目标1中，我们将以无偏倚的方式进行全局定量蛋白质组学分析，以确定与人淋巴细胞中NPM/ALK表达相关的蛋白质组学和磷酸化蛋白质组学变化。在具体目标2中，我们将确定MS衍生的NPM/ALK信号通路的选定组分的功能相关性。我们的长期目标是确定用于检测NPM/ALK阳性ALCL的稳健、灵敏和特异性蛋白质生物标志物。我们的研究对识别以ALK失调为特征的其他形式癌症的疾病生物标志物具有意义。

项目成果

Potential therapies for anaplastic lymphoma kinase-driven tumors in children: progress to date.

儿童间变性淋巴瘤激酶驱动肿瘤的潜在疗法：迄今为止的进展。

• DOI: 10.1007/s40272-013-0027-3
• 发表时间: 2013
• 期刊: Paediatric drugs
• 作者: Lowe,EricJ;Lim,MeganS
• 通讯作者: Lim,MeganS