Cellular and Biologic Origins of CLL

描述(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，其正常细胞和病因仍不清楚。这种知识鸿沟的根本是对人类记忆B细胞的生物异质性的有限认识。这些问题是确定CLL发病机制的重要挑战，因为如果不能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困难。长期目标是了解正常B细胞发育和CLL发病机制之间的联系。这项建议的目的是分析在人类记忆B细胞库中新发现的亚群的分子和功能特征，以确定正常的CLL-对应物。中心假设是具有免疫调节功能的Fc受体样(FCRL)分子大家族的成员标记CLL来源的记忆B细胞亚群。这项拟议研究的基本原理是，CLL产生的B细胞亚群的发现将为其发病机制提供新的认识，并使治疗这种无法治愈的淋巴增生性疾病的方法变得更加明智。根据我们的初步数据，这一假设将在两个特定的目标中进行验证：目标1建议确定由FCRL表达定义的记忆B细胞亚集是否在分子上类似于转化前的CLL对应细胞，目标2将研究表达记忆B细胞的FCRL的功能特征。这项研究的贡献将是重大的，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(S)，有助于阐明涉及体液免疫的未知机制，并为开发将免疫失调与癌症联系起来的预防和干预策略产生新的知识。这项拟议的研究具有创新性，因为它克服了以前选择性较差的方法，使用了具有调制功能的独特的CLL生物标记物，这些标记物定义了类似于CLL细胞的人类记忆B细胞谱系中以前未被欣赏的亚集。这一新的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。预计这些结果将产生积极影响，因为它们将为研究人员开发治疗CLL和其他B细胞疾病的预防和治疗策略提供新的途径。重要的是，这些研究将促进对体液免疫和B细胞恶性转化之间的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.