Early Predisposing Genes and Risk Stratification for CLL

慢性淋巴细胞性白血病(CLL)是成人白血病中最常见的一种，其临床转归为 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% 确诊时的患者)发展为进展性疾病的中位数为3年，总体上较差 生死存亡。相比之下，IgVn突变的儿童(诊断时占所有CLL儿童的60%)的中位数 进展时间为9.2年，有些患者从不需要治疗。造成不良后果的原因 未突变的IgVn疾病部分包括高度易感性的克隆进化。首创同一性 而IgVn未突变患者的进展事件提供了显著改善风险的潜力 分层并确定对哪些新疗法的启动和进展至关重要的新靶点 可以被开发出来。为了识别CLL中新的启动和进展事件，我们的研究小组共同 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相结合 家族倾向。这项工作证明了DNA甲基化对促凋亡细胞的下调作用 基因DAPK1。这一事件不仅是人类CLL的一般特征，而且与 家族性因素与慢性淋巴细胞性白血病的关系。我们还使用了CLL的TCL1转基因小鼠模型 它模仿IgVn未突变的人CLL，以识别参与CLL启动或 进步。在小鼠CLL中发现的分子事件被证实也在人类CLL中发生。我们 现在建议通过以下两种方式扩展我们关于这些启动和进展事件的发现 转化性实验室目标，重点是CLL中的DAPK1，以及临床目标，重点是改善风险 作为北美大型组间III期试验的一部分，对IgVn未突变的CLL进行分层。我们的 具体目的是确定：1)DAPK介导的B细胞凋亡的重要性，频率 CLL中的等位基因特异性表达，以及DAPK1基因在B细胞中表达的调控机制 细胞，特别关注可能与B细胞向CLL转化相关的调节因子；以及2) 基线和系列分子事件在无进展CLL诊断或进展中的意义 新诊断的慢性淋巴细胞性白血病患者IgVn未突变患者的生存和克隆演变。我们的整体 这一建议中的假设是，对CLL中信息和进展事件的更好理解将 为IgVn未突变的CLL提供更有效的五种风险分层方法，并为其提供新的靶点 可以开发治疗方法来潜在地防止这种疾病的克隆性进化或进展。 相关性(请参阅说明)： 该孢子翻译项目对CLL致病基因DAPK1进行了详细的研究并评估了 选择性分子事件对初诊IgVn患者无治疗生存和克隆进化的影响 没有变异的恋人。这些发现可能会改善IgVn未突变的CLL患者的进展风险 也识别靶向治疗的新靶点，以防止这种疾病的克隆性进化或进展。

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.