{"doi":"10.1002/hon.70093_82","title":"82 | CHARACTERIZING AND TARGETING FOLLICULAR LYMPHOMA'S COMMON PROGENITOR CELLS","abstract":"Introduction: Follicular lymphoma (FL) is the most common low-grade non-Hodgkin lymphoma, yet its clinical course is highly heterogeneous. While typically indolent, some patients experience frequent relapses and transformation into high-grade lymphoma, which is associated with a poor prognosis. Phylogenetic analyses of sequential FL tumors have identified common progenitor cells (CPCs), a reservoir of therapy-resistant cells that evade standard treatments and drive relapse and transformation. CPCs harbor the t(14;18) translocation and accumulate mutations in chromatin-modifying genes such as CREBBP and KMT2D. Targeting and eliminating these progenitor cells is a crucial step toward a definitive cure for FL. Methods: To investigate therapy-resistance in FL, we developed genetically engineered mouse models (BCK mice) that faithfully replicate key mutations observed in FL CPCs, including BCL2 translocation, CREBBP, and KMT2D loss-of-function mutations. These mice were treated with a mouse-adapted R-CHOP regimen (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisone), which we developed and optimized to closely mimic the human chemotherapy protocol. Through these studies, we employed single-cell RNA sequencing (scRNA-seq) and high-throughput drug screening to characterize CPC resistance mechanisms and identify potential therapeutic targets. Results: While R-CHOP treatment completely depleted B cells in wild-type mice, a therapy-resistant B-cell population persisted in BCK mice. These cells predominantly exhibited an IgM+CD80−PD-L2− memory B-cell phenotype. Single-cell RNA sequencing of CPCs revealed distinct transcriptional signatures and enriched therapeutic target pathways. Comparative analysis with human FL scRNA-seq datasets confirmed that CPC-like populations were present in FL tumors from patients with poor prognosis and early relapse. To facilitate targeted drug discovery, we employed an in vitro germinal center B-cell culture system to expand CPCs and enable high-throughput screening of epigenetic therapies. Two promising candidates, demonstrated high efficacy in vitro and in vivo, effectively eliminating R-CHOP–resistant CPCs in mice and in FL patient-derived lymphoma organoid models. Conclusions: Our findings provide deeper insights into the biology of FL progenitor cells and their role in disease relapse and progression. By identifying novel therapeutic targets and validating effective epigenetic treatments, we move closer to developing curative strategies for follicular lymphoma. Research funding declaration: Institute for Follicular Lymphoma Innovation—Idea Award. Awarded to my PhD supervisor Dinis Calado 2024. Keywords: non-Hodgkin; genomics, epigenomics, and other -omics; molecular targeted therapies No potential sources of conflict of interest.","journal":"Hematological Oncology","year":2025,"id":568582,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9626,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":368990,"name":"Letian Zhang","orcid":"0000-0002-0987-0905","position":1,"is_corresponding":false},{"id":1472862,"name":"Miu Shing Hung","orcid":"0009-0004-0412-4374","position":2,"is_corresponding":false},{"id":678935,"name":"C. Edmondson","orcid":"0000-0003-4170-2327","position":3,"is_corresponding":false},{"id":606505,"name":"J. Fitzgibbon","orcid":null,"position":4,"is_corresponding":false},{"id":1472863,"name":"Christian Reinhardt","orcid":"0000-0002-4535-3956","position":5,"is_corresponding":false},{"id":567388,"name":"Jessica Okosun","orcid":"0000-0001-6021-5044","position":6,"is_corresponding":false},{"id":1246990,"name":"Dinis Pedro Calado","orcid":"0000-0001-8239-7184","position":7,"is_corresponding":false},{"id":1269125,"name":"Oscar Atkins","orcid":null,"position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T02:56:52.212268Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}