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