Prevention of Chronic Lymphocytic Leukemia (CLL)

描述（由申请人提供）： B细胞慢性淋巴细胞白血病（CLL）是北美和欧洲最常见的白血病形式之一，约占所有病例的30%。单克隆B细胞淋巴细胞增多症（MBL）最近被认为是CLL的潜在前体，并与CLL具有相同的表型特征。血细胞计数正常的成人中有3.5%存在MBL，其中40%的受试者淋巴细胞计数将进行性增加。在具有2个或更多个CLL（家族性CLL）病例的家族中的其他健康受试者具有7倍的MBL风险。这支持了CLL和MBL发展有共同的诱发因素以及MBL可能是CLL的前体的假设。因此，我们的假设是，确定与MBL向CLL转变相关的因素，并在预后不良的侵袭性CLL高危受试者中进行侵袭性早期治疗以根除MBL，可能会预防死亡或残疾。我们认为，以MBL为中心的CLL预防策略的发展可以分三步完成。当前的应用程序是这三步流程中的第一步。在第一步中，将在初步研究中通过比较MBL细胞与CLL细胞以及通过MBL细胞群的纵向分析来鉴定可用作MBL向CLL转变的替代物的表型特征。迄今为止，我们已经分析了来自6个家族性CLL家系的45名成员的外周血样本。这些分析确定了6名MBL家族成员和2名先前未诊断的早期CLL家族成员。我们已经开发了使用流式细胞术、细胞分选和巢式PCR分析单个MBL细胞中免疫球蛋白基因的技术。我们还开发了有限数量的B细胞的微阵列分析技术。我们计划使用这些和其他技术进行试点研究，将确定与过渡到慢性淋巴细胞白血病（CLL）的样本从家族性MBL受试者的纵向分析MBL的特点。

DESCRIPTION (provided by applicant): B-cell chronic lymphocytic leukemia (CLL) is one of the most common forms of leukemia in North America and Europe, accounting for approximately 30% of all cases. Monoclonal B cell lymphocytosis (MBL) has recently been recognized as a potential precursor to CLL and shares phenotypic characteristics with CLL. MBL is present in 3.5% of adults with normal blood counts and 40% of these subjects will have progressive increases in lymphocyte counts. Otherwise healthy subjects in families with 2 or more cases of CLL (familial CLL) have a 7-fold risk of MBL. This supports the hypothesis that there are common factors predisposing to CLL and MBL development and that MBL may be a precursor for CLL. Therefore, it is our hypothesis that identification of factors associated with the transition of MBL to CLL and aggressive early therapy to eradicate MBL in subjects at high risk of developing aggressive CLL with a poor prognosis may prevent death or disability. We believe that development of CLL prevention strategies that center on MBL as a precursor to CLL can be accomplished in three steps. The current application represents the first step in this three-step process. In the first step, phenotypic characteristics that may serve as surrogates for the transition of MBL to CLL will be identified in a pilot study by comparing MBL cells to CLL cells and by longitudinal analysis of MBL cell populations. To date, we have analyzed peripheral blood samples from 45 members of 6 pedigrees with familial CLL. These analyses identified 6 family members with MBL and 2 additional members with previously undiagnosed early CLL. We have developed techniques for analysis of immunoglobulin genes in single MBL cells using flow cytometry, cell sorting and nested PCR. We have also developed techniques for microarray analysis of limited numbers of B cells. We plan to use these and other techniques to perform a pilot study that will determine characteristics of MBL that are associated with transition to CLL by longitudinal analysis of samples from familial MBL subjects.