B CLL SUBGROUPS--MATURATION STAGE AND GENE EXPRESSION

描述（申请人提供）：B型慢性淋巴细胞白血病 B-CLL是西方世界最流行的白血病。虽然B-CLL 长期以来被认为是一种同质性疾病，最近的研究表明，B-CLL病例 可根据IG V基因突变状态分为两个亚组， 基于CD 38的表面膜表达。这两个病人遵循 截然不同的临床过程未突变的IG V 基因组和那些在CD 38+经历一个更具侵略性的疾病， 几乎总是死亡，尽管广泛的化疗，远远早于 突变的IG V基因组或CD 38-组的患者。的原因 这些临床结果的差异是未知的。 本提案旨在更准确地了解这些类别的 B-CLL病例不同。我们将通过确定 中B-CLL细胞和一些其他免疫细胞的特征 这两个群体。具体而言，我们将确定：[1]表型和 B细胞活化和分化的分子特征， 每个B-CLL亚组，[2]可能解释不同的生物学特征， B-CLL亚组的临床病程，特别是两个亚组是否 的B-CLL细胞在免疫学特性如细胞因子 产生、抗原呈递、细胞信号传导和凋亡诱导 通过B细胞受体结合其他信号传导途径，和[3] 区分B-CLL的基因表达模式和水平 亚组，无论是未经处理或BCR信号转导后，如测量 基于cDNA的代表性差异分析与微阵列基因芯片 技术. 我们相信，拟议的研究将确定细胞的关键差异， 成熟，免疫功能和基因表达，这将有助于澄清 原因是他们的临床过程截然不同。希望这些 差异将提供重要的基础和临床见解， 疾病，并提出未来的预后和治疗方法。

DESCRIPTION (provided by applicant): B-type chronic lymphocytic leukemia (B-CLL) is the most prevalent leukemia in the Western world. Although B-CLL was long considered a homogeneous disease, recent studies indicate that B-CLL cases can be divided into two subgroups based on Ig V gene mutation status and also based on surface membrane expression of CD38. Patients in these two follow strikingly different clinical courses. Those patients in the unmutated Ig V gene group and those in the CD38+ experience a much more aggressive disease and almost invariably dying, despite extensive chemotherapy, much sooner than the patients in the mutated Ig V gene group or in the CD38- group. The reasons for these differences in clinical outcome are unknown. This proposal is designed to understand more precisely how these categories of B-CLL cases differ. We will address this by determining differences in the characteristics of the B-CLL cells, and some of the other immune cells, in these two groups. Specifically, we will determine: [1] the phenotypic and molecular features of B cell activation and differentiation that are unique to each B-CLL subgroup, [2] the biologic features that might explain the different clinical courses of the B-CLL subgroups, in particular whether the two subsets of B-CLL cells exhibit differences in immunologic properties such as cytokine production, antigen presentation, and cell signaling and apoptosis induction via the B cell receptor in conjunction with other signaling pathways, and [3] the patterns and levels of gene expression that distinguish the B-CLL subgroups, either unmanipulated or after BCR signaling, as measured by cDNA-based representation difference analyses and microarray gene chip technologies. We believe that the proposed studies will identify critical differences in cell maturation, immune function, and gene expression that will help clarify the reasons for their dramatically dissimilar clinical courses. Hopefully, these differences will provide important basic and clinical insights into this disease and suggest future prognostic and therapeutic approaches to it.