B CLL Subtypes--Correlation with Clinical Outcome

B CLL 亚型——与临床结果的相关性

• 批准号: 6515116
• 负责人: Neil E Kay
• 金额: $ 31.75万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6515116
• 关键词: B lymphocyte; annexins; antineoplastics; apoptosis; chronic lymphocytic leukemia; clinical research; combination chemotherapy; cyclophosphamide; cytokine receptors; fludarabine; gemcitabine; gene expression; gene mutation; human subject; immunoglobulin genes; interleukin 4; microarray technology; neoplasm /cancer genetics; neoplasm /cancer pharmacology; outcomes research

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.

描述（由申请人提供）：B细胞慢性淋巴细胞性白血病 （B-CLL）是一种常见的白血病，患者对治疗有明显变化 并且没有明确的治疗方法。但是，b-cl可能代表 由各种细胞和分子定义的独特疾病亚型 包括抗细胞凋亡的功能，染色体异常和状态 CLL B细胞克隆中的免疫球蛋白（Ig）基因的含量。具体来说，有 最近的发现，临床结果与 IG重链变量中存在或不存在体细胞突变 B-CLL克隆中的区域基因。确定原因的确切生物学特征 两个B-CLL患者子组的表现不同是未知的。更多的 重要的是，迄今为止尚未在IG突变状态之间建立相关性 以及特定的治疗策略，应答率和关键的生物学和 分子特征，例如凋亡，药物敏感性和染色体 异常。因此，在此建议中，我们将表征凋亡， 细胞遗传学异常和种系的基因表达谱与 体细胞突变类型B-CLL克隆，更重要的是，我们将直接 将这些分子参数与临床结果与治疗相关。我们的 具体的假设是，这些关键区分的一个或多个 B-CLL克隆将使我们能够预测疾病的进展和治疗性 CLL子集中的响应。为了检验这一假设，我们将进行实验室 B-CLL的两项北部中央癌症治疗组临床试验的研究： 一项旨在测试氟达拉滨在交替的试验 基于环磷酰胺至先前未经治疗的CLL患者；还有另一个 它使用吉西他滨用于先前治疗的CLL患者。具体来说，我们 提议1）确定B-CLL Ig Ig VH基因区域状态之间的关系 以及白血病所表现出的关键生物学，遗传和分子特征 克隆; 2）检查临床反应参数的关联 接受氟达拉滨和环磷酰胺或吉西他滨治疗的患者 克隆生物学和分子特征。

项目成果

Identification of a global gene expression signature of B-chronic lymphocytic leukemia.

• 发表时间: 2003-03
• 期刊: Molecular cancer research : MCR
• 作者: D. Jelinek;R. Tschumper;G. Stolovitzky;S. Iturria;Y. Tu;J. Lepre;Nigam H. Shah;N. Kay