Proteomic biomarkers of ALK+ lymphoma

描述（由申请人提供）：间变性大细胞淋巴瘤（ALCL）是一种独特的外周t细胞淋巴瘤亚型，包含涉及ALK酪氨酸激酶的染色体易位。ALCL约占所有儿童非霍奇金淋巴瘤（NHL）的10%。t(2;5)（p23;q35）染色体畸变导致嵌合癌基因核磷蛋白间变性淋巴瘤激酶（NPM/ALK）的过度表达，是这些肿瘤中最常见的易位。NPM/ALK蛋白在ALCL淋巴瘤形成中起关键作用，并已被证明在体外和体内引起淋巴细胞恶性肿瘤。虽然，儿童局部ALCL的预后很好，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%的患儿病情发展到晚期，25%-35%的ALCL患儿会复发或对初始治疗变得难治性。ALCL的生物标志物可用于诊断，早期发现，预测生物行为和治疗是必要的。对于难治性/复发性ALCL儿童和诊断时预后较差的儿童亚群，需要新的靶向治疗。在本应用中，我们建议利用一套基于定量质谱的蛋白质组学策略，并辅以复杂的生物信息学方法来鉴定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，我们将以公正的方式进行全球定量蛋白质组学分析，以确定人类淋巴样细胞中与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，我们将建立ms衍生的NPM/ALK信号通路中选定成分的功能相关性。我们的长期目标是鉴定出检测NPM/ alk阳性alcl的稳健、敏感和特异性的蛋白质生物标志物。我们的研究对其他形式的以ALK失调为特征的癌症的疾病生物标志物的鉴定具有启示意义。

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.