B CLL Subtypes--Correlation with Clinical Outcome

描述（由申请人提供）：B细胞慢性淋巴细胞白血病 （B-CLL）是一种常见的白血病，患者对治疗存在显著差异 并且没有明确的治疗方法。然而，B-CLL可能代表了 由多种细胞和分子生物学特性定义的不同疾病亚型 特征包括细胞凋亡抵抗、染色体异常和状态 免疫球蛋白（IG）基因在CLL B细胞克隆。具体来说有 最近的研究发现，临床结果与 IG重链可变区是否存在体细胞突变 B-CLL克隆中的区域基因。决定为什么 两个B-CLL患者亚组的治疗如此不同尚不清楚。更 重要的是，迄今为止还没有发现IG突变状态 和具体的治疗策略，反应率，以及关键的生物和 分子特征，如细胞凋亡、药物敏感性和染色体 异常因此，在本提案中，我们将描述细胞凋亡， 细胞遗传学异常和基因表达谱的生殖系与 体细胞突变型B-CLL克隆，更重要的是，我们将直接 将这些分子参数与治疗的临床结果相关联。我们 具体假设是，这些关键区别特征中的一个或多个 B-CLL克隆将使我们能够预测疾病进展和治疗 CLL亚群中的应答。为了验证这一假设，我们将进行实验室 在两项B-CLL的北中央癌症治疗组临床试验中进行的研究： 一项试验旨在测试氟达拉滨对交替给药的疗效， 对既往未经治疗的CLL患者使用环磷酰胺;以及 其将吉西他滨用于先前治疗的CLL患者。我们特别 建议1）确定B-CLL IG VH基因区状态 以及白血病患者所表现出的关键生物学、遗传学和分子特征。 克隆;和2）检查临床反应参数之间的关联， 接受氟达拉滨和环磷酰胺或吉西他滨治疗的患者， 克隆生物学和分子生物学特征。

DESCRIPTION (provided by applicant): B-cell chronic lymphocytic leukemia (B-CLL) is a common leukemia with significant patient variability to therapy and without a definitive curative approach. However, B-CLL likely represents distinct disease subtypes defined by a variety of cellular and molecular features including apoptosis resistance, chromosomal abnormalities, and status of immunoglobulin (Ig) genes in the CLL B cell clones. Specifically, there are recent findings that a strong relationship exists between clinical outcome and the presence or absence of somatic mutations in the Ig heavy chain variable region genes in the B-CLL clone. The exact biologic features that determine why the two B-CLL patient subgroups fare so differently are unknown. More importantly, no correlation to date has been made between Ig mutation status and specific therapeutic strategies, response rates, and key biologic and molecular features such as apoptosis, drug sensitivities, and chromosomal abnormalities. In this proposal, therefore, we will characterize apoptosis, cytogenetic abnormalities, and gene expression profiles of germline versus somatic mutation type B-CLL clones and more importantly, we will directly correlate these molecular parameters with clinical outcome to therapy. Our specific hypothesis is that one or more of these key discriminating features of B-CLL clones will allow us to predict disease progression and therapeutic response in CLL subsets. To test this hypothesis, we will conduct laboratory studies in two North Central Cancer Treatment Group clinical trials for B-CLL: one trial designed to test the efficacy of Fludarabine given on an alternating basis with cyclophosphamide to previously untreated CLL patients; and the other which uses Gemcitabine for previously treated CLL patients. Specifically, we propose to 1) determine the relationship between B-CLL Ig VH gene region status and key biological, genetic, and molecular features exhibited by the leukemic clone; and 2) examine the association between clinical response parameters for patients treated with fludarabine and cyclophosphamide or Gemcitabine and clonal biologic and molecular features.