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

总体摘要 尽管我们在了解慢性淋巴细胞的生物学和治疗方面取得了长足的进步 过去十年的白血病(CLL)、里希特综合征(RS)或CLL向侵袭性转化 在慢性淋巴细胞性白血病患者的临床护理中，淋巴瘤仍然是一个未得到满足的领域。RS带来的挑战 要求采用大规模的跨学科方法来更全面地将基因组和蛋白质水平的特征联系起来 具有细胞行为，从而使基于分子的诊断方案更加准确和敏感，并且更加有效 这种毁灭性疾病的治疗方法是可以设计出来的。我们的假设是基因组和表观基因组 变化定义了从CLL到RS的轨迹，并且存在不同的RS亚型，导致了不同的 表型行为。我们的方法解决了理解RS构建自强项的挑战 我们在CLL研究方面的高度互动性和多学科项目。在过去的资助期内，我们有 成功地生成了迄今为止最大的CLL‘图谱’，整合了遗传、转录和甲基组数据 从1000多个CLL样本中进行临床注释，以发现具有临床意义的疾病亚型和 新奇的驾驶员改装。根据这些信息，我们还产生了遗传上忠实的CLL小鼠模型 反映人类疾病，定义疾病动力学和治疗耐药性的模式，并确定新的 治疗上的弱点。在未来5年，我们将利用我们计划产生的新资源， 从计算读数到功能读数、遗传读数和表型读数，以应对 理解并解决后援问题。因此，我们的愿景是，我们将为 了解疾病转化的不同生物学和疾病的亚型，并执行功能 对小分子和免疫治疗剂的反应的分析，可以整合并导致 这种疾病的检测和治疗模式发生了转变。这些具有高度翻译性的倡议具有很强的 由核心领导的专业知识提供支持。因此，我们的首要目标是彻底改变临床 患有这种毁灭性疾病的患者的结局，并利用从该计划中发现的信息来 激励合理设计下一代RS的个性化甚至根治性疗法。

OVERALL ABSTRACT Although we have made great strides in our understanding of the biology and treatment of chronic lymphocytic leukemia (CLL) over the past decade, Richter's syndrome (RS) or the transformation of CLL to aggressive lymphoma remains an area of unmet need in the clinical care of CLL patients. The challenges presented by RS mandate large-scale interdisciplinary approaches to more completely link genomic and protein-level features with cellular behavior so that more precise and sensitive molecular-based diagnostic schema and more effective treatments for this devastating disease can be devised. Our hypothesis is that genomic and epigenomic alterations define the trajectory from CLL to RS and that distinct subtypes of RS exist, leading to distinct phenotypic behaviors. Our approach to address the challenge of understanding RS builds from the strengths of our highly interactive and multi-disciplinary program in CLL research. Over the last funding period, we have succeeded in generating the largest CLL `map' to date, integrating genetic, transcriptomic and methylome data with clinical annotation from over 1000 CLL samples to discover clinically meaningful subtypes of disease and novel driver alterations. From this information, we have also generated genetically-faithful CLL mouse models reflective of human disease, defined patterns of disease kinetics and therapeutic resistance, and identified new therapeutic vulnerabilities. Over the next 5 years, we will leverage the new resources generated by our Program, ranging from computational to functional, genetic and phenotypic readouts, to confront the challenge of understanding and addressing RS. Thus, our vision is that we will enact a precision approach for understanding the distinct biology of disease transformation and the subtypes of disease, and perform functional analyses of responses to small molecules and immunotherapy agents, that could be integrated and lead to a paradigm shift in the detection and treatment for this disease. These highly translational initiatives are strongly supported by the expertise of the Core Leaders. Our overarching goal is thus to revolutionize the clinical outcomes of patients with this devastating disease and to utilize the information discovered from this Program to motivate the rational design of the next generation of personalized and even curative therapies for RS.