Tracing the Evolution of Chronic Lymphocytic Leukemia to Richter's Syndrome: Defining Transformation

追踪慢性淋巴细胞白血病向里氏综合征的演变：定义转变

• 批准号: 10425791
• 负责人: Erin M Parry
• 金额: $ 18.9万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10425791
• 关键词: Accounting; Admixture; Advisory Committees; Automobile Driving; B lymphoid malignancy; B-Lymphocytes; Biological; Biological Process; Biology; Cancer Biology; Cell Line; Cells; Chronic Lymphocytic Leukemia; Clinical; Clinical Data; Communities; Computational Biology; DNA; Dana-Farber Cancer Institute; Data; Detection; Development; Development Plans; Diagnosis; EZH2 gene; Environment; Epigenetic Process; Event; Evolution; Foundations; Gene Expression; Genes; Genetic; Genetic Transcription; Genomics; Goals; Indolent; Institutes; International; Knowledge; Laboratories; Lymphoma; Malignant Neoplasms; Mentors; Mentorship; Modernization; Molecular; Molecular Genetics; Mutation; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Physicians; Process; Recurrence; Research; Research Personnel; Resources; Richter' s Syndrome; Sampling; Scientist; Signal Transduction; Specimen; Structure; Techniques; Testing; Therapeutic; Training; Variant; Work; analytical tool; base; cancer genetics; career; career development; cohort; design; disorder control; epigenetic regulation; exome sequencing; functional genomics; genome sequencing; improved; improved outcome; insight; large cell Diffuse non-Hodgkin' s lymphoma; leukemic transformation; next generation; novel; patient subsets; prognostic significance; prognostication; sample collection; statistics; therapy resistant; tissue archive; transcriptome; transcriptomics; translational scientist; tumor; whole genome

Project Summary / Abstract Recent advances have transformed the treatment landscape of chronic lymphocytic leukemia (CLL) and improved patient outcomes. However, the transformation of CLL to Richter’s syndrome (RS) remains a major barrier to disease control and limits survival. In CLL, genomic studies have advanced understanding of the driving molecular events and biological pathways that underlie CLL development, progression and therapeutic resistance, and enabled advances in clinical prognostication and tailored therapeutic approaches. In contrast to CLL, the genetic basis of RS remains largely uncharacterized. Over the last few years, an analytic framework was designed to overcome obstacles in the analysis of RS samples, including accounting for admixed CLL and RS DNA and detecting copy number changes from archival tissue. As a result, pipelines have been established to identify the CLL and RS clones and trace the evolution of CLL to RS. Using this approach, analysis of 40 RS patient samples has been completed, leading to the identification of novel RS drivers, including disruption of genes encoding epigenetic modifiers. Based on this preliminary data, Dr. Parry hypothesizes that recurrent genetic and epigenetic driver events underlie the transition of CLL to RS and that the identification of RS drivers will advance understanding of the biological pathways that drive transformation. To test this hypothesis, she seeks to define the genetic drivers of RS through the comprehensive characterization of ~150 RS cases using whole exome sequencing and trace the evolution of CLL to RS (Aim 1). In Aim 2, she will identify the epigenetic drivers of RS and examine how the transcriptome changes upon transformation to RS. In Aim 3, she will examine the functional impact of recurrent RS drivers to yield insights into the cellular changes of transformation. This research will provide a molecular definition of RS and identify biological mechanisms of transformation, and thus, is a crucial step towards the goal of improving outcomes for patients with RS. Dr. Parry has outlined a detailed five-year career development plan to meet her goal of becoming an independent investigator focused on the biology and genetics of transformed lymphoma. In order to achieve this goal, she has formed an Advisory Committee of mentors in cancer genetics, lymphoma biology and functional genomics to provide her with detailed scientific and career mentorship. Additionally, she has formed collaborative relationships with internationally recognized experts in computational biology, genomics, epigenetics, statistics and CLL biology to provide her with project guidance, experimental input and training. The Dana-Farber Cancer Institute is an ideal environment for Dr. Parry to achieve her career goals and execute her scientific plan, given the world-renowned research community and strong focus on training the next-generation of independent physician-scientists. Dr. Parry will have all the necessary resources to complete her proposed project and achieve her goal of becoming an independent laboratory-based translational investigator.

项目总结/摘要 最近的进展已经改变了慢性淋巴细胞白血病（CLL）的治疗前景， 改善患者结局。然而，CLL向里希特综合征（RS）的转化仍然是一个主要的研究领域。 疾病控制的障碍，并限制生存。在慢性淋巴细胞白血病中，基因组研究已经加深了对驱动细胞凋亡的理解。 CLL发生、进展和治疗基础的分子事件和生物学途径 耐药性，并使临床诊断和定制治疗方法的进展成为可能。相比 CLL，RS的遗传基础仍然在很大程度上未被表征。在过去的几年里，一个分析框架 旨在克服RS样品分析中的障碍，包括混合CLL和 RS DNA和检测档案组织的拷贝数变化。因此，管道已经建立， 鉴定CLL和RS克隆并追踪CLL到RS的进化。使用这种方法，分析40个RS 患者样本已经完成，导致识别新的RS驱动程序，包括破坏 编码表观遗传修饰物的基因。根据这些初步数据，帕里博士假设， 遗传和表观遗传驱动事件是CLL向RS过渡的基础， RS驱动程序将促进对驱动转化的生物途径的理解。为了验证这一 假设，她试图通过综合表征~150 RS病例使用全外显子组测序并追踪CLL向RS的演变（目的1）。在目标2中，她将确定 RS的表观遗传驱动因素，并研究转录组如何在转化为RS后发生变化。在目标3中， 她将研究经常性RS驱动程序的功能影响，以深入了解细胞的变化， 转型这项研究将提供RS的分子定义，并确定RS的生物学机制。 因此，转型是实现改善RS患者预后目标的关键一步。Parry医生 已经制定了一个详细的五年职业发展计划，以实现她成为一名独立人士的目标。 研究人员专注于转化淋巴瘤的生物学和遗传学。为了实现这一目标，她 成立了一个顾问委员会，由癌症遗传学、淋巴瘤生物学和功能基因组学方面的导师组成。 为她提供详细的科学和职业指导。此外，她还与 与国际公认的计算生物学、基因组学、表观遗传学、统计学专家的关系 和CLL生物学为她提供项目指导，实验输入和培训。Dana-Farber癌症 研究所是Parry博士实现其职业目标和执行其科学计划的理想环境， 世界知名的研究社区和强烈的重点是培养下一代独立的 物理科学家帕里博士将有所有必要的资源来完成她提出的项目， 实现她的目标，成为一个独立的实验室为基础的翻译研究。