Role of the BCR in B Cell Chronic Lymphocytic Leukemia

BCR 在 B 细胞慢性淋巴细胞白血病中的作用

• 批准号: 7561345
• 负责人: Diane F Jelinek
• 金额: $ 31.35万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7561345
• 关键词: Address; Affinity; Aliquot; Alleles; Antibodies; Antigens; Apoptosis; B-Cell Activation; B-Lymphocytes; Behavior; Biochemical; Biological; Biology; Biopsy; Bone Marrow; Categories; Cell Survival; Cell physiology; Cells; Cellular biology; Characteristics; Chromosome abnormality; Chronic Lymphocytic Leukemia; Classification; Clinic; Clinical; Clinical Data; Clinical Research; Clonal Evolution; Clonal Expansion; Coculture Techniques; Collecting Cell; Commit; Complementarity Determining Region III; Country; Cryopreserved Cell; Cytogenetics; DNA Sequence Rearrangement; Data; Databases; Development; Disease; Disease Outcome; Elderly; Enzymes; Epitopes; Etiology; Evaluation; Event; Exclusion; Exhibits; Flow Cytometry; Frequencies; Genes; Genetic; Genomic Instability; Growth; Heavy-Chain Immunoglobulins; Heterogeneity; Human; IGH@ gene cluster; Immunoglobulin Somatic Hypermutation; Immunoglobulin Variable Region; In Vitro; Indolent; Leukemic Cell; Link; Longitudinal Studies; Malignant - descriptor; Marrow; Measures; Mediating; Memory; Mining; Molecular; Molecular Abnormality; Morbidity - disease rate; Mutate; Mutation; Outcome; Patients; Peptide Phage Display Library; Peptides; Physiological; Play; Population; Positioning Attribute; Prognostic Factor; Prognostic Marker; Property; Protein Microchips; Proteins; Publishing; Quality of life; RNA Interference; Reading Frames; Receptor Signaling; Receptors, Antigen, B-Cell; Research Ethics Committees; Risk; Role; Sampling; Sampling Studies; Screening procedure; Signal Transduction; Signaling Molecule; Staging; Stereotyping; Stratification; Stromal Cells; Testing; Time; Vial device; base; cell bank; cell growth; cohort; complementarity-determining region 3; density; design; experience; follow-up; in vivo; inhibitor/antagonist; insight; interest; leukemia; lymph nodes; molecular phenotype; mortality; novel; novel therapeutic intervention; prognostic; public health relevance; receptor; receptor expression; receptor-mediated signaling; response; variable region gene

DESCRIPTION (provided by applicant): B cell chronic lymphocytic leukemia (B-CLL) is the most common form of leukemia among older adults in Western countries and is a significant cause of morbidity and mortality in the older adult population. We believe the B cell receptor (BCR) plays a crucial role in dictating the behavior of the malignant clone in B-CLL and in turn dictates clinical behavior of B-CLL. Our data and that obtained by others provide compelling evidence that the use of specific immunoglobulin heavy chain variable region (IGHV) genes in CLL is non-random and the IGH complementarity determining region 3 (CDR3) is remarkably homologous in certain CLL patients. In addition, the somatic hypermutation (SHM) status of the IGHV gene in the leukemic cell BCR is now a validated and powerful prognostic factor. Regardless of SHM status, all CLL B cells more closely resemble antigen experienced memory rather than naive B cells and some CLL B cells display a molecular phenotype which is similar to BCR-stimulated normal B cells. These observations collectively support the hypothesis that antigenic stimulation influences the development and/or course of B-CLL. Several broad questions concerning the biological role of the BCR in this disease remain unanswered. First, does the BCR continue to play an ongoing role in the biology of B-CLL, and if so, is this uniformly displayed by all patient leukemic B cells? Two, do CLL B cells expressing stereotyped BCRs recognize similar antigens, and if so, does this feature permit insight into the etiology of this disease and can this information be used to devise timely novel therapeutic interventions? Third, what is the relationship between molecular features of the BCR and clinical outcome? We are uniquely positioned to answer these questions because of our exceptional access to primary CLL B cells and an extensive cell bank of over 3000 cryopreserved vials of high quality cells collected as a result of our ongoing efforts to determine the IGHV molecular features of B-CLL patients, now numbering over 1000 patients. In addition, these data are integrated into a clinical data base which features invaluable long term clinical outcome data on each patient as well as expression levels of other biologically relevant molecules with prognostic significance and cytogenetic (FISH) data characterizing the most common CLL-associated genetic abnormalities. Thus, to answer these questions and test our unifying hypothesis that the BCR is functional and plays a critical role in the biology of malignant B cells in B-CLL and clinical outcome of this disease, we propose a comprehensive experimental strategy that will: i) systematically link BCR mediated signaling competencies with molecular BCR features that are critical for in vivo leukemic B cell survival, growth, and accumulation over time; ii) investigate BCR antigen recognition and identify shared epitopes recognized by CLL B cells expressing canonical receptors; and iii) probe the relevance of the BCR to the leukemic B cell process in CLL by correlating various IGHV molecular features with patient clinical outcome and other prognostic factors via our access to an invaluable clinical and research database. PUBLIC HEALTH RELEVANCE: B cell chronic lymphocytic leukemia is a very common leukemia in this country and is currently incurable. Because at least 70 percent of all patients will ultimately require treatment in order to have an enhanced quality of life, avoidance of complications of the disease, and increased survival, we are committed to better understanding the underlying mechanisms that contribute to leukemic cell growth and survival in the patients. This proposal will take a comprehensive approach to define the role of the leukemic B cell antigen receptor in determining the behavior of the malignant B cells and how this in turn dictates patient clinical outcome. Through these studies, we aim to add novel insight into the etiology of this disease and are optimistic that this information can be used to devise timely novel therapeutic interventions.

描述（由申请人提供）：B细胞慢性淋巴细胞白血病（B-CLL）是西方国家老年人中最常见的白血病形式，也是老年人发病和死亡的重要原因。我们相信 B 细胞受体 (BCR) 在决定 B-CLL 中恶性克隆的行为方面发挥着至关重要的作用，进而决定了 B-CLL 的临床行为。我们的数据和其他人获得的数据提供了令人信服的证据，证明 CLL 中特定免疫球蛋白重链可变区 (IGHV) 基因的使用是非随机的，并且 IGH 互补决定区 3 (CDR3) 在某些 CLL 患者中显着同源。此外，白血病细胞 BCR 中 IGHV 基因的体细胞超突变 (SHM) 状态现已成为经过验证的强大预后因素。无论 SHM 状态如何，所有 CLL B 细胞都更类似于抗原经历过的记忆，而不是幼稚 B 细胞，并且一些 CLL B 细胞表现出与 BCR 刺激的正常 B 细胞相似的分子表型。这些观察结果共同支持了抗原刺激影响 B-CLL 的发展和/或病程的假设。关于 BCR 在这种疾病中的生物学作用的几个广泛问题仍未得到解答。首先，BCR 是否继续在 B-CLL 生物学中发挥持续作用，如果是，所有患者白血病 B 细胞是否一致表现出这一作用？第二，表达定型 BCR 的 CLL B 细胞是否识别相似的抗原，如果是，这一特征是否允许深入了解该疾病的病因学，并且该信息是否可用于设计及时的新型治疗干预措施？第三，BCR的分子特征与临床结果之间的关系是什么？我们在回答这些问题方面拥有得天独厚的优势，因为我们能够获得原代 CLL B 细胞，并且拥有一个包含 3000 多瓶冷冻保存的高质量细胞的广泛细胞库，这些细胞是我们不断努力确定 B-CLL 的 IGHV 分子特征而收集的患者数量目前已超过1000人。此外，这些数据被整合到一个临床数据库中，该数据库包含每位患者的宝贵的长期临床结果数据以及具有预后意义的其他生物学相关分子的表达水平和表征最常见的 CLL 相关遗传的细胞遗传学 (FISH) 数据。异常。因此，为了回答这些问题并测试我们的统一假设，即 BCR 是有功能的，并且在 B-CLL 中恶性 B 细胞的生物学和该疾病的临床结果中发挥关键作用，我们提出了一种全面的实验策略，该策略将：系统地将 BCR 介导的信号传导能力与 BCR 分子特征联系起来，这些特征对于体内白血病 B 细胞的存活、生长和积累至关重要； ii) 研究 BCR 抗原识别并识别表达经典受体的 CLL B 细胞识别的共享表位； iii) 通过访问宝贵的临床和研究数据库，将各种 IGHV 分子特征与患者临床结果和其他预后因素相关联，探讨 BCR 与 CLL 中白血病 B 细胞过程的相关性。 公共卫生相关性：B 细胞慢性淋巴细胞白血病是该国一种非常常见的白血病，目前无法治愈。由于至少 70% 的患者最终需要治疗，以提高生活质量、避免疾病并发症并提高生存率，因此我们致力于更好地了解有助于白血病细胞生长和生存的潜在机制在患者中。该提案将采用综合方法来定义白血病 B 细胞抗原受体在确定恶性 B 细胞行为中的作用，以及这反过来如何决定患者的临床结果。通过这些研究，我们的目标是为这种疾病的病因学提供新的见解，并乐观地认为这些信息可用于及时设计新颖的治疗干预措施。