Biological Definition of FCRL Molecules in Malignancy

FCRL 分子在恶性肿瘤中的生物学定义

• 批准号: 7530536
• 负责人: RANDALL S DAVIS
• 金额: $ 19.58万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7530536
• 关键词: B cell differentiation; B lymphoid malignancy; B-Lymphocytes; Biological; Biological Assay; Biological Markers; Biology; Biometry; Cell Lineage; Cell surface; Cells; Chronic Lymphocytic Leukemia; Clinical; Collaborations; Country; Data; Defect; Detection; Diagnosis; Diagnostic; Disease; Disease Progression; Exhibits; Family; Family member; Fc Receptor; Flow Cytometry; Gene Family; Genotype; Goals; Heavy-Chain Immunoglobulins; Hybridomas; IgG Receptors; Immunity; Immunoglobulin Variable Region; Individual; Indolent; Institutes; Jaw; Laboratories; Lead; Long Island; Lymphoproliferative Disorders; Malignant Neoplasms; Medical Research; Medical center; Memory; Methods; Molecular Biology; Monoclonal Antibodies; Mutate; Mutation; Mutation Analysis; Pathogenesis; Patient Care; Patients; Pattern; Phenotype; Procedures; Process; Prognostic Marker; Protein Overexpression; Proteins; Public Health; Research; Role; Sampling; Scientist; Screening procedure; Signal Transduction; Somatic Mutation; Staining method; Stains; Standardization; Stratification; Subgroup; Surface; Surrogate Markers; Techniques; Testing; Therapeutic; Therapeutic Intervention; Thinking; Time; Tyrosine; University Hospitals; University of Alabama at Birmingham Cancer Center; Validation; Western World; Work; ZAP-70 Gene; base; clinical phenotype; cohort; disorder subtype; experience; field study; fluorophore; follower of religion Jewish; improved; insight; leukemia; novel; outcome forecast; prognostic; receptor; skills; syk Family Tyrosine Kinase; variable region gene

DESCRIPTION (provided by applicant): B cell chronic lymphocytic leukemia (B-CLL), the most prevalent leukemia in Western countries, is characterized by two subtypes that differ in the mutation status of their immunoglobulin heavy-chain variable region (IgVH) gene. While patients with mutated IgVH genes (MT-CLL) typically have an indolent disease course of greater than 25 years with minimal therapeutic intervention, individuals harboring unmutated IgVH genes (UM-CLL) experience a more aggressive process with a median survival of 8 years even after intensive treatment. Despite these differences, B-CLL cells transcriptionally and phenotypically resemble memory B lineage cells. As genotyping of IgVH regions is costly and technically challenging for most clinical laboratories, surrogate markers for mutation status are being investigated. Expression of the ZAP-70 Syk family tyrosine kinase was found to best correlate with UM-CLL, enabling the stratification of patients into indolent or more aggressive cohorts; however, analysis of this cytoplasmic marker by flow cytometry has created technical challenges resulting in diagnostic variability. The identification of a family of Fc receptor-like molecules (FCRL1-5) with distinct B cell expression and tyrosine-based signaling function opens a new field of study. The long term goal of our studies is to determine the biological role of FCRL molecules in normal immunity and investigate how their functions may be subverted in malignancy. Our preliminary data indicate preferential overexpression of four of five FCRL proteins on MT-CLL. Notably, flow cytometric analysis of the surface expression of FCRL2 on >100 UM-CLL and MT-CLL cell samples indicated strong concordance with MT-CLL and an ability to predict early time to therapy. We hypothesize that FCRL2 can be used as a surrogate prognostic marker in B-CLL and that flow cytometric analysis of cell surface expression of FCRL2 will not only provide a robust assay suitable for clinical laboratories, but will also extend the capabilities of B-CLL diagnosis. This will be tested in two Specific Aims: 1) Optimization of FCRL2 detection on B-CLL cells by flow cytometry and standardization of the assay; and 2) Internal and external validation of the prognostic importance of FCRL2 expression for predicting IgVH mutation status and disease progression in B-CLL. Significance: The assessment of FCRL2 surface expression using routine clinical flow cytometry assays could greatly facilitate prognosis in B-CLL and, thus, significantly improve the overall care of patients with this leukemia. In addition, we anticipate that these studies will extend the capabilities of B-CLL prognosis by providing new insights concerning the aggressive subtype, which ultimately could assist in determination of the optimal timing of therapeutic intervention. PUBLIC HEALTH RELEVANCE: This proposal will investigate the expression of a recently described family of Fc receptor-like molecules (FCRL) in the most prevalent leukemia in Western countries, B cell chronic lymphocytic leukemia (B-CLL). FCRL proteins appear to be preferentially overexpressed in the indolent form of the disease. This work will investigate whether some of these molecules may serve as novel prognostic markers in B-CLL and replace or supplement current indicators of disease aggressiveness.

描述（申请人提供）：B细胞慢性淋巴细胞白血病（B-CLL）是西方国家最常见的白血病，其特征在于免疫球蛋白重链可变区（IgVH）基因突变状态不同的两种亚型。虽然携带突变 IgVH 基因 (MT-CLL) 的患者在最少的治疗干预下通常会出现超过 25 年的惰性病程，但携带未突变 IgVH 基因 (UM-CLL) 的患者会经历更具侵袭性的过程，即使在强化治疗后，中位生存期也为 8 年。尽管存在这些差异，B-CLL 细胞在转录和表型上与记忆 B 谱系细胞相似。由于 IgVH 区域的基因分型对于大多数临床实验室而言成本高昂且技术上具有挑战性，因此正在研究突变状态的替代标记。研究发现 ZAP-70 Syk 家族酪氨酸激酶的表达与 UM-CLL 具有最佳相关性，从而能够将患者分为惰性组或更具攻击性组；然而，通过流式细胞术分析这种细胞质标记物带来了技术挑战，导致诊断变异性。具有独特 B 细胞表达和基于酪氨酸的信号传导功能的 Fc 受体样分子家族 (FCRL1-5) 的鉴定开辟了一个新的研究领域。我们研究的长期目标是确定 FCRL 分子在正常免疫中的生物学作用，并研究它们的功能在恶性肿瘤中如何被破坏。我们的初步数据表明 MT-CLL 上五种 FCRL 蛋白中的四种优先过表达。值得注意的是，对超过 100 个 UM-CLL 和 MT-CLL 细胞样本上 FCRL2 表面表达的流式细胞术分析表明与 MT-CLL 高度一致，并且能够预测早期治疗时间。我们假设 FCRL2 可用作 B-CLL 的替代预后标志物，并且 FCRL2 细胞表面表达的流式细胞术分析不仅会提供适合临床实验室的稳健检测，而且还将扩展 B-CLL 诊断的能力。这将在两个具体目标中进行测试：1) 通过流式细胞术优化 B-CLL 细胞的 FCRL2 检测和测定标准化； 2) FCRL2 表达对于预测 B-CLL 中 IgVH 突变状态和疾病进展的预后重要性的内部和外部验证。意义：使用常规临床流式细胞术测定 FCRL2 表面表达可以极大地促进 B-CLL 的预后，从而显着改善这种白血病患者的整体护理。此外，我们预计这些研究将通过提供有关侵袭性亚型的新见解来扩展 B-CLL 预后的能力，最终有助于确定治疗干预的最佳时机。公共健康相关性：该提案将研究最近描述的 Fc 受体样分子 (FCRL) 家族在西方国家最常见的白血病——B 细胞慢性淋巴细胞白血病 (B-CLL) 中的表达。 FCRL 蛋白似乎在疾病的惰性形式中优先过度表达。这项工作将研究其中一些分子是否可以作为 B-CLL 的新型预后标志物，并取代或补充当前疾病侵袭性的指标。