Role of the BCR in B Cell Chronic Lymphocytic Leukemia

描述(申请人提供)：B细胞慢性淋巴细胞白血病(B-CLL)是西方国家老年人中最常见的白血病形式，是老年人发病和死亡的重要原因。我们认为B细胞受体(BCR)在决定B-CLL恶性克隆的行为中起着关键作用，进而决定了B-CLL的临床行为。我们的数据和其他人的数据提供了令人信服的证据，证明在某些CLL患者中，特异性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)具有显著的同源性。此外，白血病细胞BCR中IGHV基因的体细胞高突变(SHM)状态现在被证实是一个强有力的预后因素。无论SHM状态如何，所有CLL B细胞都更接近于抗原经验记忆，而不是原始B细胞，一些CLL B细胞表现出类似于BCR刺激的正常B细胞的分子表型。这些观察结果共同支持这样的假设，即抗原刺激影响B-CLL的发展和/或进程。关于bcr在这种疾病中的生物学作用的几个广泛的问题仍然没有答案。首先，BCR是否继续在B-CLL的生物学中发挥作用，如果是，这是否在所有患者的白血病B细胞中统一显示？第二，表达刻板的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这种疾病的病因，这些信息是否可以用于设计及时的新的治疗干预措施？第三，BCR的分子特征与临床结局之间的关系是什么？我们在回答这些问题上具有得天独厚的优势，因为我们可以获得原代CLL B细胞，并且拥有广泛的细胞库，其中包含3000多瓶冷冻保存的高质量细胞，这是我们不断努力确定B-CLL患者IGHV分子特征的结果，目前已有1000多名患者。此外，这些数据被整合到临床数据库中，其中包括每个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相关分子的表达水平，以及表征最常见的CLL相关遗传异常的细胞遗传学(FISH)数据。因此，为了回答这些问题并检验我们的统一假设，即BCR是有功能的，并在B-CLL的恶性B细胞的生物学和这种疾病的临床结局中发挥关键作用，我们提出了一个全面的实验策略，该策略将：i)系统地将BCR介导的信号能力与分子BCR特征联系起来，这些特征对体内白血病B细胞的存活、生长和随时间积累至关重要；ii)研究BCR抗原识别并鉴定表达典型受体的CLL B细胞识别的共同表位；以及iii)通过访问宝贵的临床和研究数据库，将各种IGHV分子特征与患者的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。公共卫生意义：B细胞慢性淋巴细胞性白血病是一种非常常见的白血病，目前是无法治愈的。由于至少70%的患者最终将需要治疗，以提高生活质量，避免疾病并发症，并提高存活率，我们致力于更好地了解有助于患者白血病细胞生长和存活的潜在机制。这项建议将采用全面的方法来确定白血病B细胞抗原受体在决定恶性B细胞行为中的作用，以及这如何反过来决定患者的临床结果。通过这些研究，我们的目标是增加对这种疾病的病因的新见解，并乐观地认为这些信息可以用于设计及时的新的治疗干预措施。

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.