Comprehensive dissection of the CLL genome and phenome to improve patient outcomes

项目摘要 遗传和表观遗传学特征的巨大异质性在任何癌症类型和 随着分辨率的提高，个体肿瘤内的肿瘤已经被记录在案。值得注意的是，肿瘤内部的异质性， 它助长了克隆进化并产生了治疗耐药性，已被确定为最重要的障碍 为持久的治愈干杯。慢性淋巴细胞性白血病(CLL)就是如此，这是一种成熟B细胞的一种最初无痛的恶性肿瘤 随着时间的推移不可避免地变得更具侵袭性的细胞，其临床过程在不同的地方差异很大 个人。尽管最近批准了针对关键CLL的高效力药物(即ibrutinib、idelalisib) 耐药途径，耐药性--有时与治疗期间高度侵袭性的复发有关-- 已经上报了。这种疾病的异质性带来的挑战要求大规模的跨学科研究。 将基因组特征与细胞行为联系起来的方法，以便有效的个性化治疗可以 精心设计的。我们的假设是，CLL具有异质性但连贯的基因组改变，导致不同的 表型行为，受到进化选择压力的影响，这会影响个体的疾病轨迹。 拟议计划的成员有成功的合作记录，以使 对我们理解CLL做出了里程碑式的贡献。尽管我们对CLL和 针对它的有效治疗手段的不断扩大，是我们对 这一疾病将需要在功能强大的系列中跨数据层的网络级集成，以全面 绘制CLL的电路图(项目1、2)，以及评估基因组影响的系统方法 预后和治疗反应的变化(项目2、3)。当然，传统的方法是 由于缺乏可靠的细胞系和小鼠模型，对CLL基因损伤的功能性研究一直受到限制 以及广泛承认的在遗传操作原代CLL细胞方面的困难。直通主修 分析CLL方法的创新，由每个项目负责人带头，范围从 通过计算原代人类B细胞的功能遗传和非遗传读数，我们很好地- 准备协同解决CLL中的临床相关问题。这些倡议是强有力的 在核心领导的共同专业知识的支持下，预计将向我们提供有关合理设计 下一代慢性淋巴细胞性白血病的个性化和根治性治疗。

Project Summary The vast heterogeneity of genetic and epigenetic features both among samples from any cancer type and within individual tumors has been documented with increasing resolution. Of note, intratumoral heterogeneity, which fuels clonal evolution and generates treatment resistance, has been identified as the foremost obstacle to lasting cure. This is true of chronic lymphocytic leukemia (CLL), an initially indolent malignancy of mature B cells which inevitably becomes more aggressive over time, and whose clinical course is highly variable across individuals. Despite the recent approval of highly potent drugs (i.e. ibrutinib, idelalisib) that target key CLL pathways, drug resistance—sometimes associated with highly aggressive relapse while on treatment—has been reported. The challenges presented by this disease heterogeneity mandate large-scale interdisciplinary approaches to link genomic features with cellular behavior so that effective personalized treatments can be devised. Our hypothesis is that CLL has heterogeneous yet coherent genomic alterations leading to distinct phenotypic behaviors, subject to evolutionary selective pressures, which impact individual disease trajectories. The members of the proposed Program have a successful track record of collaborating together to make landmark contributions to our understanding of CLL. Despite our growing knowledge about CLL and the expanding armamentarium of effective therapeutics targeting it, the next quantum leap in our understanding of this disease will require network-level integration across data layers in well-powered series to comprehensively map the circuitry of CLL (Projects 1, 2), and systematic approaches to evaluate the impact of genomic alterations on prognosis and response to therapy (Projects 2, 3). Certainly, conventional approaches to functionally study genetic lesions of CLL have been limited by the lack of faithful cell lines and mouse models and by the widely acknowledged difficulties in genetically manipulating primary CLL cells. Through major innovations in approaches to dissect CLL, spearheaded by each Project Leader and ranging from computational to functional genetic and non-genetic based readouts in primary human B cells, we are well- poised to synergize together to address clinically relevant questions in CLL. These initiatives are strongly supported by the joint expertise of the Core Leaders and are expected to inform us on the rational design of the next generation of personalized and curative therapies for CLL.