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，其染色体易位涉及ALK酪氨酸激酶。ALCL约占儿童非霍奇金淋巴瘤(NHL)的10%。T(2；5)(p23；q35)染色体异常导致的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淋巴肿瘤的发生中起关键作用，并在体外和体内被证明引起淋巴系统恶性肿瘤。虽然局限型儿童ALCL预后良好，5年生存率为90-95%，但晚期ALCL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，25%-35%的ALCL儿童将复发或对最初的治疗无效。需要对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。对于难治性/复发性ALCL的儿童和确诊时预后较差的儿童，需要新的靶向治疗。在这一应用中，我们建议利用一套基于定量质谱学的蛋白质组学策略，并辅之以复杂的生物信息学方法来识别NPM/ALK阳性淋巴瘤的蛋白质组生物标记物。在特定的目标1中，我们将以公正的方式进行全球定量蛋白质组分析，以确定与NPM/ALK在人淋巴样细胞中表达相关的蛋白质组和磷酸蛋白质组的变化。在具体目标2中，我们将确定MS来源的NPM/ALK信号通路的部分组件的功能相关性。我们的长期目标是为检测NPM/ALK阳性的ALCL寻找可靠、敏感和特异的蛋白质生物标志物。我们的研究对识别以碱性磷酸酶去调节为特征的其他形式的癌症的疾病生物标志物具有重要意义。 公共卫生相关性：卫生保健的影响。晚期ALCL的儿童仅有约60%的5年无事件生存率，晚期复发是常见的并发症。由于70%的儿童患有晚期疾病，25%-35%的ALCL儿童将复发或对最初的治疗无效。需要对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。此外，对于难治性/复发性ALCL儿童和确诊时预后较差的儿童亚群，需要新的靶向治疗。在这一应用中，我们建议利用一套基于定量质谱学的蛋白质组学策略，并辅之以复杂的生物信息学方法来识别NPM/ALK阳性淋巴瘤的蛋白质组生物标记物。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。总而言之，我们的研究将导致识别NPM/ALK淋巴瘤的蛋白质生物标记物，这将对ALCL患者的诊断、治疗和监测至关重要。

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.