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

项目摘要 来自任何癌症类型的样本中遗传和表观遗传特征的巨大异质性， 在单个肿瘤内的变化已经被越来越多的分辨率记录下来。值得注意的是，瘤内异质性， 它促进克隆进化并产生治疗抗性，已被确定为最重要的障碍 持久治愈。慢性淋巴细胞性白血病（CLL）是一种成熟B细胞的初始惰性恶性肿瘤， 随着时间的推移，这些细胞不可避免地变得更具侵略性，并且其临床过程在不同的人中高度可变。 个体尽管最近批准了靶向关键CLL的高效药物（即伊曲替尼、艾代拉里斯）， 途径，耐药性-有时与治疗期间高度侵袭性复发相关- 被举报。这种疾病异质性所带来的挑战要求大规模的跨学科 将基因组特征与细胞行为联系起来的方法， 设计的我们的假设是，CLL具有异质性但一致的基因组改变，导致不同的 表型行为，受到进化选择压力，影响个体疾病轨迹。 拟议计划的成员有一个成功的合作记录， 为我们理解CLL做出了里程碑式的贡献。尽管我们对CLL的了解越来越多， 扩大针对它的有效疗法的医疗设备，这是我们理解的下一个飞跃。 这种疾病将需要在功能强大的系列中跨数据层进行网络级集成， 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 改变预后和对治疗的反应（项目2，3）。当然，传统的方法 由于缺乏可靠的细胞系和小鼠模型，CLL遗传病变的功能研究受到限制 以及广泛承认的遗传操作原代CLL细胞的困难。通过重大 由每个项目负责人带头的CLL剖析方法创新， 计算到功能性遗传和非遗传基础的读数在原代人类B细胞，我们是很好的- 准备协同合作以解决CLL中的临床相关问题。这些举措有力地 在核心领导人的共同专业知识的支持下，预计将为我们提供有关合理设计的信息， 下一代CLL的个性化和治愈性疗法。

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.