Large-scale technology and advanced computational analyses have revolutionized our understanding of the genomic underpinnings of lymphoma subtypes across the board, providing near-complete genomic encyclopedias. A characteristic feature of indolent lymphomas is their propensity to initially respond to therapeutic intervention, only to subsequently relapse or transform to a more aggressive lymphoma at a later stage. As a consequence, the population disease burden remains significant as, for the majority, their lymphomas are incurable. There is growing evidence that persisting cancer-repopulating cells act as lymphoma reservoirs and are the harbingers for lymphoma recurrence and therapy resistance. Follicular lymphoma (FL) is the best studied of the indolent B-cell lymphomas and represents a tractable model system given its protracted clinical course. The evidence for the existence of a tumor-propagating reservoir in FL (referred to as the common precursor cell, CPC) has primarily arisen from genetic studies in two key areas. The first are unique cases of donor-derived lymphomas, where both donor and recipient of stem cell transplants develop clonally related FL several years later, suggesting precursor cells were transferred at the time of the transplantation. The second include studies of temporal genetic profiling of sequential diagnostic, relapsed, and transformed FL (tFL) tumors from the same individual, undertaken by us and others more recently using higher-resolution next-generation sequencing. This has allowed us to infer the genetic composition of these putative ancestral or reservoir populations and indeed determine that epigenetic alterations such as mutations in the histone-modifying enzymes, CREBBP and KMT2D, represent early lymphoma-initiating events. Recent genomic studies in histologically related entities such as pediatric-type FL and in situ follicular neoplasia (ISFN) have provided further clues to the relevance of the genetic events. A number of crucial questions remain: What is the exact origin, phenotype, and niche of these reservoir populations, and do particular patient-specific niches promote a degree of dormancy and continued molecular evolution of these lymphoma reservoirs? Capturing the characteristics and behavior of these reservoir populations in FL has the potential to reveal novel biomarkers and facilitate new approaches to measuring, monitoring, and tracking this population. Furthermore, defining the characteristics of these populations would allow the generation of murine models that more suitably recapitulate this disease state, providing a resource to guide and test rational novel therapies. In conclusion, we now have early insights into the genetic fingerprints of these persisting tumor-propagating reservoir populations. Targeting these populations, perceived as the “root'' of the cancer, may provide our best chance of preventing relapse and realizing a cure for FL.

Citation Format: Jessica Okosun. Defining lymphoma reservoirs: Clues from the genomics [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr IA38.