Validating a novel biomarker of clinical progression and survival in CLL

验证 CLL 临床进展和生存的新型生物标志物

• 批准号: 8177052
• 负责人: RANDALL S DAVIS
• 金额: $ 36.46万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-19 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8177052
• 关键词: Age; Aggressive behavior; Aggressive course; Antigens; B-Cell Development; Biological Assay; Biological Markers; Biology; Cells; Chronic Lymphocytic Leukemia; Clinic; Clinical; Clinical Treatment; Clinical Trials Design; Country; Cytoplasm; DNA Sequence; Data; Detection; Diagnosis; Diagnostic; Differentiated Gene; Disease; Disease Progression; Early treatment; Fc Receptor; Flow Cytometry; Genetic; Goals; Gold; Heavy-Chain Immunoglobulins; Heterogeneity; Hospitals; Immunoglobulin Somatic Hypermutation; Immunoglobulin Variable Region; Incidence; Individual; Indolent; Laboratories; Lead; Memory B-Lymphocyte; Methodology; Mission; Mutate; Mutation; Outcome; Pathogenesis; Patients; Prognostic Marker; Proteins; Protocols documentation; Public Health; Publishing; Qualifying; Reagent; Receptors, Antigen, B-Cell; Relapse; Research; Research Personnel; Resistance; Risk Factors; Staining method; Stains; Surface; Surrogate Markers; Testing; Therapeutic; Time; Treatment Efficacy; Ursidae Family; Validation; Work; ZAP-70 Gene; analytical tool; base; clinical Diagnosis; clinical practice; clinically relevant; cost; disorder subtype; hospital laboratories; improved; innovation; insight; leukemia; novel; novel marker; outcome forecast; prognostic; receptor; variable region gene

DESCRIPTION (provided by applicant): Prognostic markers that can discriminate between aggressive and indolent forms of B cell chronic lymphocytic leukemia (CLL) have provided remarkable insight into the clinical heterogeneity of the disease and are influencing the design of clinical trials, but the technical complexity and variability in assaying these indicators have presented challenges for hospital laboratories. The most significant breakthrough in the field was the discovery that CLL can be segregated into two major subtypes that differ in their clinical aggression according to the degree of somatic hypermutation in the immunoglobulin heavy-chain variable region (IGHV) gene. Individuals with mutated IGHV genes (MT-CLL) have a median survival that is three times longer than patients with unmutated IGHV genes (UM-CLL). Because sequencing IGHV regions is costly and impractical for clinical labs, most hospitals now analyze CD38 and ZAP-70 using flow cytometry given their preferential expression by UM-CLL cells. Although both proteins are significantly associated with a poor prognosis, they are ~25-30% discordant with IGHV mutation status. Furthermore, because ZAP-70 is located in the cytoplasm, its staining can vary and protocols to evaluate it are not yet standardized. The long term goal is to investigate the pathogenesis of CLL. The overall objective of this proposal is to validate the clinical utility of a novel biomarker of CLL prognosis. Our central hypothesis is that Fc receptor-like 2 (FCRL2), a unique indicator of indolent MT-CLL, will more accurately predict IGHV mutation status and clinical progression than other currently employed prognostic markers. This hypothesis is based on: (i) our recently published findings that FCRL2 robustly predicts IGHV mutation status and clinical progression in CLL, (ii) newly developed preliminary data outlined in the Research Strategy, and (iii) independent work by other investigators that supports this hypothesis. The rationale for the proposed research is that optimization and validation of FCRL2 detection on CLL cells will facilitate its wide application and improve prognostic accuracy over existing indicators. We plan to test the central hypothesis by pursuing the following specific aims: 1) Optimize the detection of FCRL2 on CLL cells by flow cytometry and 2) Validate and qualify the prognostic utility of FCRL2 in predicting IGHV mutation status, clinical disease progression, and survival in CLL. In Aim 1, we will optimize newly developed reagents for detecting FCRL2. In Aim 2, we will use these analytical tools to validate the utility of FCRL2 in predicting IGHV mutation status and clinical outcome. The proposed research is innovative, because it focuses on a surface receptor distinctly upregulated on MT-CLL cells that provides the highest concordance with IGHV status. This contribution will be significant because it will advance currently established approaches to prognostication in CLL by improving accuracy, consistency, ease of use, and cost. The use of FCRL2 will change the approach to CLL prognostication at diagnosis, have collective benefits when used with other markers, and is anticipated to ultimately modify approaches to clinical treatment in the most common leukemia in Western countries. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because it will develop and validate a robust new marker capable of improving clinical diagnosis and prognosis beyond currently established indicators in the most common leukemia in Western countries, B cell chronic lymphocytic leukemia (CLL). This work will be important to NIH's mission because it will have broad impact and direct translational application that advances diagnostic, prognostic, and therapeutic strategies for CLL patients.

描述（由申请人提供）：可以区分侵袭性和惰性形式的B细胞慢性淋巴细胞白血病（CLL）的预后标志物为该疾病的临床异质性提供了显着的见解，并影响临床试验的设计，但分析这些指标的技术复杂性和可变性给医院实验室带来了挑战。该领域最重要的突破是发现CLL可以根据免疫球蛋白重链可变区（IGHV）基因的体细胞高突变程度分为两种主要亚型，这两种亚型的临床攻击性不同。IGHV基因突变的个体（MT-CLL）的中位生存期是IGHV基因未突变的患者（UM-CLL）的三倍。由于测序IGHV区域对于临床实验室来说是昂贵且不切实际的，因此大多数医院现在使用流式细胞术分析CD 38和ZAP-70，因为它们优先表达于UM-CLL细胞。虽然这两种蛋白质都与不良预后显著相关，但它们与IGHV突变状态的差异约为25-30%。此外，由于ZAP-70位于细胞质中，其染色可以变化，并且评估其的方案尚未标准化。长期目标是研究CLL的发病机制。该提案的总体目标是验证CLL预后的新型生物标志物的临床效用。我们的中心假设是，Fc受体样2（FCRL 2），一个惰性MT-CLL的独特指标，将更准确地预测IGHV突变状态和临床进展比其他目前采用的预后标志物。这一假设基于：（i）我们最近发表的研究结果，即FCRL 2可以有力地预测CLL中的IGHV突变状态和临床进展，（ii）研究策略中概述的新开发的初步数据，以及（iii）支持这一假设的其他研究人员的独立工作。拟议研究的基本原理是，对CLL细胞的FCRL 2检测的优化和验证将促进其广泛应用，并提高现有指标的预后准确性。我们计划通过追求以下具体目标来检验中心假设：1）通过流式细胞术优化CLL细胞上FCRL 2的检测，和2）验证和鉴定FCRL 2在预测CLL中IGHV突变状态、临床疾病进展和存活中的预后效用。在目标1中，我们将优化新开发的用于检测FCRL 2的试剂。在目标2中，我们将使用这些分析工具来验证FCRL 2在预测IGHV突变状态和临床结果中的效用。拟议的研究是创新的，因为它专注于MT-CLL细胞上明显上调的表面受体，该受体与IGHV状态具有最高的一致性。这一贡献将是显著的，因为它将通过提高准确性、一致性、易用性和成本来推进目前建立的CLL中的自动化方法。FCRL 2的使用将改变CLL诊断的方法，当与其他标志物一起使用时具有集体效益，并预计最终改变西方国家最常见白血病的临床治疗方法。 公共卫生相关性：这项拟议的研究与公共卫生有关，因为它将开发和验证一种强大的新标志物，该标志物能够改善西方国家最常见的白血病B细胞慢性淋巴细胞白血病（CLL）的临床诊断和预后。这项工作将是重要的NIH的使命，因为它将有广泛的影响和直接的翻译应用，先进的诊断，预后和治疗策略的慢性淋巴细胞白血病患者。