Core 1 Abstract Given the poor prognosis for patients with chronic lymphocytic leukemia (CLL) who develop Richter syndrome (RS), an expanded molecular understanding of RS is critical both to understand which patients are at greatest risk and to develop improved therapeutic strategies. There is currently no effective standard of care therapy for RS patients, and this is likely to be a growing problem, as increasing numbers of CLL patients treated with novel agents are living longer, putting them at risk of developing RS. The fundamental mission of Core 1 is to ensure a robust tissue resource of clinically- annotated primary samples from patients with RS treated both on and off clinical trials. Additionally, we will maximize opportunities to procure matched CLL samples—highly feasible because of our long- established deep CLL sample repository-- so that clonal relationships between RS and antecedent CLL, and molecular and functional differences between these two related entities, can be studied. We will also continue our systematic banking of cell and plasma samples from all CLL patients seen at our center. We will emphasize banking those at high risk for developing RS, both prior to any evidence of transformation and at the time their CLL has progressed to RS, for evaluation of cell-free DNA as a method of early detection. In this fashion, the resources of this Core will supply the Projects with the necessary primary RS and CLL tissue to understand the genesis, biology, and most promising therapeutic targets in RS. We have established the infrastructure and a coordinated workflow to obtain fresh RS biopsies both from patients enrolled on treatment trials and those treated outside the trial setting. We have well-established systems to efficiently distribute cellular and nucleic acid material across the Program, for deep molecular profiling as described in the Projects. We have further coordinated with external clinical trial sites to share processing SOPs so that biopsy material can be obtained and processed in a uniform fashion across studies and institutions. We already have sufficient RS patient samples in our BioBanks to allow us to immediately begin to generate data through the Projects. Through the efforts detailed in this Core section, we plan to significantly increase the availability of such samples to fuel the science of the Projects throughout the timeline of this award and beyond. These efforts will provide a firm foundation for future translation of the research findings into potential novel biomarkers of RS development, as well as the biology of RS itself and its potential therapeutic vulnerabilities, thereby facilitating the development of novel clinical trials.