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）是最常见的成人白血病类型，其临床结果是 很大程度上是由 IgVn 基因突变状态预测的。 IgVn 未突变状态的患者（占所有患者的 40%） 诊断时的患者）平均在 3 年内出现进展性疾病，并且总体状况较差 生存。相比之下，IgVn 突变患者（诊断时所有 CLL 患者的 60%）的中位值 进展时间为 9.2 年，有些患者从未需要治疗。不良结果的原因 IgVn 未突变疾病部分包括克隆进化的高度倾向。启动的识别 IgVn 非突变患者的进展事件有可能显着降低风险 分层，并确定对新疗法的启动和进展至关重要的新靶点 可以开发。为了确定 CLL 中新的起始和进展事件，我们的研究小组共同努力 采用了两种新颖的策略。第一个将 DNA 甲基化分析与遗传研究结合起来 家族倾向。这项工作证明了促凋亡细胞的 DNA 甲基化下调 基因 DAPK1。该事件不仅是人类 CLL 的一般特征，而且与 罹患 CLL 的家族倾向。我们还使用了 TCL1 转基因小鼠 CLL 模型 模拟 IgVn 未突变的人类 CLL，以识别参与 CLL 启动的其他分子事件或 进展。在小鼠 CLL 中发现的分子事件被证实也发生在人类 CLL 中。我们 现在建议通过以下两种方式扩展我们与这些起始和进展事件相关的发现： 转化实验室目标，重点关注 CLL 中的 DAPK1，临床目标，重点关注改善风险 作为大型北美组间 III 期试验的一部分，对 IgVn 非突变 CLL 进行分层。我们的 具体目标是确定：1​​) DAPK 介导的 B 细胞凋亡的重要性、发生频率 CLL 中的等位基因特异性表达，以及 B 中 DAPK1 基因表达的调节机制 细胞，特别关注与 B 细胞转化为 CLL 潜在相关的调节因子；和 2） 基线和系列分子事件在 CLL 起始或无进展进展中的意义 新诊断的 IgVn 非突变疾病 CLL 患者的生存和克隆进化。我们的整体 该提案中的假设是，提高对 CLL 起始和进展事件的理解将会 导致针对 IgVn 非突变 CLL 更有效的风险分层方法，以及新的目标 可以开发治疗方法来潜在地预防这种疾病的克隆进化或进展。 相关性（参见说明）： 该 SPORE 转化项目对 CLL 起始基因 DAPK1 进行了详细研究并评估 选择分子事件对新诊断 IgVn 的无治疗生存和克隆进化的影响 未突变的患者。这些发现可能会提高 IgVn 非突变 CLL 患者的进展风险 还确定了靶向治疗的新靶点，以防止这种疾病的克隆进化或进展。