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细胞慢性淋巴细胞性白血病（B-CLL）是西方国家老年人中白血病最常见的形式，是老年人群体发病和死亡率的重要原因。我们认为，B细胞受体（BCR）在决定B-CLL中恶性克隆的行为方面起着至关重要的作用，进而决定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，表明在CLL中使用特定的免疫球蛋白重链变量区域（IGHV）基因是非随机的，而确定区域3（CDR3）的IGH互补性在某些CLL患者中是非常同源的。此外，白血病细胞BCR中IGHV基因的体细胞超数（SHM）状态现在是经过验证且强大的预后因素。不管SHM状态如何，所有CLL B细胞都更类似于抗原的记忆，而不是天真的B细胞，而某些CLL B细胞显示出类似于BCR刺激的正常B细胞​​的分子表型。这些观察结果共同支持以下假设：抗原刺激影响B-CLL的发展和/或过程。关于BCR在该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在B-CLL的生物学中是否继续发挥持续的作用，如果是这样，这是否由所有患者白血病B细胞均匀地显示出来？第二，表达定型BCR的CLL B细胞是否识别类似的抗原，如果是这样，此功能是否可以深入了解该疾病的病因，并且该信息是否可以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有什么关系？由于我们不断努力确定B-CLL患者的IGHV分子特征，目前已有超过3000多个高质量细胞收集的高质量细胞，现在我们有特殊的访问原代CLL B细胞的途径，因此我们有独特地回答这些问题的独特位置。此外，这些数据被整合到临床数据库中，该数据基于每个患者的宝贵长期临床结果数据以及其他具有预后意义和细胞遗传学（FISH）数据的其他生物学相关分子的表达水平，这些数据表征了最常见的CLL相关遗传异常。因此，要回答这些问题并检验我们的统一假设，即BCR具有功能性，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起着至关重要的作用，我们提出了一种全面的实验策略，该策略将：i）系统地将BCR介导的信号能力与分子BCR的特征联系起来，这些特征与分子BCR对Vivo Leuk Bepect bection Bcr的成长至关重要。 ii）研究BCR抗原识别并鉴定出表达规范受体的CLL B细胞识别的共同表位； iii）通过将各种IGHV分子特征与患者的临床结果和其他预后因素相关联，通过我们获得宝贵的临床和研究数据库，探测了BCR与CLL白血病B细胞过程的相关性。 公共卫生相关性：B细胞慢性淋巴细胞性白血病是该国非常普遍的白血病，目前无法治愈。由于至少有70％的患者最终将需要治疗才能增强生活质量，避免疾病并发症以及增加的生存率，因此我们致力于更好地理解有助于有助于白血病细胞生长的基本机制和患者的生存。该建议将采用一种全面的方法来定义白血病B细胞抗原受体在确定恶性B细胞行为以及这如何决定患者临床结果中的作用。通过这些研究，我们旨在增加对该疾病病因的新颖见解，并乐观地认为该信息可用于设计及时的新型治疗干预措施。