Cellular and Biologic Origins of CLL

描述（由申请人提供）：B细胞慢性淋巴细胞白血病（CLL）是西方国家最常见的白血病，其正常细胞对应物和病因尚不清楚。这种知识差距的基础是对人类记忆B细胞的生物学异质性的有限认识。这些问题是确定CLL发病机制的重要挑战，因为如果不更彻底地了解这种关系，改进预防、诊断、治疗和疫苗接种策略将继续是困难的。长期目标是了解正常B细胞发育与CLL发病机制之间的联系。本提案的目的是分析人类记忆B细胞库中新发现的亚群的分子和功能特征，以定义正常的cll对应物。中心假设是具有免疫调节功能的Fc受体样（FCRL）分子大家庭的成员标记了CLL起源于的记忆B细胞亚群。这项研究的基本原理是发现CLL产生的B细胞亚群，将为其发病机制提供新的认识，并为治疗这种无法治愈的淋巴增生性疾病提供更多的信息。基于我们的初步数据，这一假设将在两个特定目标中得到验证：目标1提出确定由FCRL表达定义的记忆B细胞亚群在分子上是否与转化前的CLL对应体相似；目标2将研究表达FCRL的记忆B细胞的功能特征。这项研究的贡献将是显著的，因为它将提供对新发现的记忆B细胞亚群的全面分析，首次揭示CLL的细胞起源，有助于阐明未探索的体液免疫机制，并为开发将免疫失调与癌症联系起来的预防和干预策略提供新的知识。所提出的研究具有创新性，因为它通过使用具有调节功能的CLL独特生物标志物来克服以前选择性较低的方法，这些生物标志物定义了人类记忆B细胞库中以前未被发现的类似CLL细胞的亚群。这种新策略将揭示这些细胞的分子和功能特征，改变我们对记忆B细胞多样性的认识，帮助发现CLL对应物，并促进对其发病机制的理解。这些结果有望产生积极的影响，因为它们将为研究人员提供新的途径，以制定治疗CLL和其他B细胞疾病的预防和治疗策略。重要的是，这些研究应该促进对体液免疫和B细胞恶性转化之间动态界面的基本理解。

DESCRIPTION (provided by applicant): The normal cellular counterpart and etiology of B cell chronic lymphocytic leukemia (CLL), the most common leukemia in Western counties, still remains unknown. Fundamental to this knowledge gap is a limited awareness of the biological heterogeneity of human memory B cells. These issues are important challenges for determining CLL pathogenesis because without a more thorough understanding of this relationship, improving prevention, diagnostic, treatment, and vaccination strategies will continue to be difficult. The long-term goal is to understand the link between normal B cell development and the pathogenesis of CLL. The objective of this proposal is to analyze the molecular and functional features of newfound subpopulations in the human memory B cell repertoire to define the normal CLL-counterpart. The central hypothesis is that members of an extended family of Fc receptor-like (FCRL) molecules with immunoregulatory function mark subsets of memory B cells from which CLL derives. The rationale for the proposed research is that the discovery of the B cell subpopulation from which CLL arises will provide new appreciation of its pathogenesis and enable more informed approaches for treating this incurable lymphoproliferative disorder. Based on our preliminary data, this hypothesis will be tested in two specific aims: Aim 1 proposes to determine whether a memory B cell subset defined by FCRL expression molecularly resembles the pre-transformed CLL counterpart and Aim 2 will investigate the functional characteristics of FCRL expressing memory B cells. The contribution of this research will be significant because it will provide a comprehensive analysis of newfound memory B cell subpopulations to reveal for the first time the cellular origin(s) of CLL, help elucidate unexplored mechanisms involved in humoral immunity, and generate new knowledge for developing preventive and interventional strategies that link immune dysregulation and cancer. The proposed research is innovative because it overcomes previous less selective approaches by employing unique biomarkers of CLL possessing modulatory function that define previously unappreciated subsets in the human memory B cell repertoire resembling CLL cells. This novel strategy, will disclose molecular and functional features of these cells, shift our recognition of memory B cell diversity, assist in unearthing the CLL counterpart, and advance understanding of its pathogenesis. These outcomes are expected to have a positive impact because they will provide new avenues for researchers to develop preventative and therapeutic strategies for the treatment of CLL and other B cell disorders. Importantly, these studies should advance fundamental understanding of the dynamic interface between humoral immunity and the malignant transformation of B cells.