Early Predisposing Genes and Risk Stratification for CLL

CLL 的早期易感基因和风险分层

• 批准号: 7715167
• 负责人: ALBERT DE LA CHAPELLE
• 金额: $ 28.93万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7715167
• 关键词: Alleles; American; Apoptosis; Apoptotic; B-Lymphocytes; Cancer and Leukemia Group B; Chlorambucil; Chronic; Clinical; Clinical Trials; Clonal Evolution; DAP kinase; DNA; DNA Methylation; Data; Development; Diagnosis; Disease; Disease Progression; Down-Regulation; Early treatment; Enrollment; Event; Experimental Leukemia; Family; Gene Expression; Gene Frequency; Genes; Genetic; Human; Human Characteristics; Immunoglobulins; Inferior; Instruction; Laboratories; Lead; Mediating; Molecular; Molecular Abnormality; Mus; Mutate; Natural History; Newly Diagnosed; Outcome; Patients; Phase III Clinical Trials; Phosphotransferases; Predisposition; Process; Progression-Free Survivals; Progressive Disease; Proteins; Randomized; Regulation; Relative (related person); Reproduction spores; Research; Risk; Sampling; Staging; Stratification; Susceptibility Gene; Symptoms; Therapeutic; Time; Transgenic Mice; Work; adult leukemia; base; cell transformation; chronic leukemia; clinically relevant; clinically significant; fludarabine; high risk; improved; interest; leukemia; mouse model; novel; novel strategies; outcome forecast; prevent; response; rituximab

Chronic lymphocyfic leukemia (CLL) is the most common type of adult leukemia whose clinical outcome is predicted in great part by the IgVn gene mutational status. Patients with IgVn un-mutated status (40% of all pafients at diagnosis) develop progressive disease at a median of 3 years and have inferior overall survival. In contrast, IgVn mutated pafients (60% of all CLL pafients at diagnosis) have a median progression time of 9.2 years, with some patients never requiring therapy. Reasons for adverse outcome in IgVn un-mutated disease include in part a high predisposifion to clonal evolufion. Idenfificafion of initiafion and progression events in IgVn un-mutated patients offers the potential to substantially improve risk stratification and also to idenfify novel targets crucial to initiation and progression for which new therapies can be developed. To identify novel initiating and progression events in CLL, our research groups together have employed two novel strategies. The first combines DNA methylation analysis with genetic studies of familial predisposition. This work demonstrated down-regulafion by DNA methylation of the pro-apoptotic gene DAPK1. This event not only is a general characteristic of human CLL but also is associated with familial predisposifion to developing CLL. We also have used the TCL1 transgenic mouse model of CLL that mimics IgVn un-mutated human CLL to identify addifional molecular events involved in CLL initiafion or progression. Molecular events identified in murine CLL were confirmed to also occur in human CLL. We now propose to expand our findings relative to these initiation and progression events through both a translational laboratory aim, focused on DAPK1 in CLL, and a clinical aim, focused on improving risk stratificafion in IgVn un-mutated CLL as part of a large North American Intergroup Phase III trial. Our specific aims are to determine: 1) the importance of DAPK-mediated apoptosis in B-cells, frequency of allele-specific expression in CLL, and mechanisms by which DAPK1 gene expression is regulated in B- cells, with particular focus on regulators potentially relevant to B-cell transformation to CLL; and 2) the significance of baseline and serial molecular events in CLL inifiafion or progression on progression-free survival and clonal evolution in newly diagnosed CLL patients with IgVn un-mutated disease. Our overall hypothesis in this proposal is that improved understanding of inifiafing and progression events in CLL will lead to more effecfive risk stratified approaches for IgVn un-mutated CLL, and also novel targets for which therapies can be developed to potentially prevent clonal evolution or progression of this disease. RELEVANCE (See instructions): This SPORE translational project performs detailed study of the CLL inifiating gene DAPK1 and assesses the impact of select molecular events on treatment free survival and clonal evolution in newly diagnosed IgVn un-mutated pafients. These findings may improve risk of progression of IgVn un-mutated CLL patients and also idenfify novel targets for targeted therapies to prevent clonal evolution or progression of this disease.

慢性淋巴细胞白血病（CLL）是成人白血病中最常见的类型，其临床结局是 在很大程度上由IgVn基因突变状态预测。IgVn未突变状态的患者（所有患者中的40%） 诊断时的患者）在中位3年时发生疾病进展， 生存相比之下，IgVn突变患者（诊断时所有CLL患者的60%）的中位 进展时间为9.2年，一些患者从未需要治疗。不良结局的原因 IgVn未突变疾病部分包括克隆进化的高倾向性。识别初始化 IgVn未突变患者中的进展事件提供了实质性改善风险的可能性 分层，也证实了新的目标至关重要的启动和进展，新的治疗 可以开发。为了识别CLL中新的启动和进展事件，我们的研究小组共同努力 采用了两种新颖的策略。第一种方法是将DNA甲基化分析与基因研究相结合， 家族倾向这项工作证明了通过DNA甲基化下调促凋亡基因， DAPK 1基因。该事件不仅是人类CLL的一般特征，而且与以下相关： CLL的家族易感性我们还使用了CLL的TCL 1转基因小鼠模型 其模拟IgVn未突变的人CLL以鉴定参与CLL起始的另外的分子事件，或 进展确认在鼠CLL中鉴定的分子事件也发生在人CLL中。我们 现在，我建议通过以下两个方面来扩展我们关于这些起始和进展事件的发现： 转化实验室目标，侧重于CLL中的DAPK 1，临床目标，侧重于改善风险 作为大型北美组间III期试验的一部分，在IgVn未突变的CLL中进行分层。我们 具体的目的是确定：1）DAPK介导的细胞凋亡在B细胞中的重要性， CLL中等位基因特异性表达，以及DAPK 1基因表达在B- 细胞，特别关注可能与B细胞转化为CLL相关的调节因子;和2） 基线和系列分子事件在CLL感染或进展中对无进展的意义 IgVn未突变疾病的新诊断CLL患者的存活率和克隆进化。我们的整体 该建议中的假设是，对CLL中的inifiafing和进展事件的更好理解将 导致IgVn未突变CLL的更有效的风险分层方法，以及新的靶点， 可以开发治疗方法以潜在地防止这种疾病的克隆进化或进展。 相关性（参见说明）： 这个孢子翻译项目进行了详细的研究CLL inifiating基因DAPK 1和评估 选择分子事件对新诊断IgVn患者无治疗生存期和克隆进化的影响 未变异的病人这些发现可以改善IgVn未突变的CLL患者的进展风险， 还证实了靶向治疗的新靶点，以防止这种疾病的克隆进化或进展。