B CLL Subtypes--Correlation with Clinical Outcome

描述(申请人提供)：B细胞慢性淋巴细胞性白血病 (B-CLL)是一种常见的白血病，患者对治疗有很大的变异性 而且没有明确的治疗方法。然而，B-CLL可能代表 由多种细胞和分子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细胞克隆中的表达。具体地说，有 最近的研究发现，在临床结果和 免疫球蛋白重链变量是否存在体细胞突变 B-CLL克隆中的区域基因。确切的生物特征决定了为什么 这两个B-CLL患者亚组的情况差异如此之大，目前尚不清楚。更多 重要的是，到目前为止，免疫球蛋白突变状态之间还没有相关性 和特定的治疗策略、应答率和关键的生物和 细胞凋亡、药物敏感性和染色体等分子特征 异常现象。因此，在这项提案中，我们将描述细胞凋亡的特征， 生殖系VS的细胞遗传学异常和基因表达谱 体细胞突变B-CLL克隆，更重要的是，我们将直接 将这些分子参数与临床治疗结果相关联。我们的 具体的假设是，这些关键的区分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子集中的响应。为了验证这一假设，我们将进行实验室 北中癌症治疗组治疗B-CLL的两项临床试验研究： 一项旨在测试氟达拉滨交替给药疗效的试验 对未经治疗的慢性淋巴细胞性白血病患者给予环磷酰胺基础治疗；另一 它使用吉西他滨治疗先前治疗的CLL患者。具体来说，我们 建议1)确定B-CLL Ig VH基因区域状态的关系 以及白血病表现出的关键的生物学、遗传学和分子特征 克隆；以及2)检查临床反应参数之间的关联 氟达拉滨、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.