{"doi":"10.1038/s41375-021-01181-w","title":"BET proteolysis targeted chimera-based therapy of novel models of Richter Transformation-diffuse large B-cell lymphoma","abstract":"Richter Transformation (RT) develops in CLL as an aggressive, therapy-resistant, diffuse large B cell lymphoma (RT-DLBCL), commonly clonally-related (CLR) to the concomitant CLL. Lack of available pre-clinical human models has hampered the development of novel therapies for RT-DLBCL. Here, we report the profiles of genetic alterations, chromatin accessibility and active enhancers, gene-expressions and anti-lymphoma drug-sensitivity of three newly established, patient-derived, xenograft (PDX) models of RT-DLBCLs, including CLR and clonally-unrelated (CLUR) to concomitant CLL. The CLR and CLUR RT-DLBCL cells display active enhancers, higher single-cell RNA-Seq-determined mRNA, and protein expressions of IRF4, TCF4, and BCL2, as well as increased sensitivity to BET protein inhibitors. CRISPR knockout of IRF4 attenuated c-Myc levels and increased sensitivity to a BET protein inhibitor. Co-treatment with BET inhibitor or BET-PROTAC and ibrutinib or venetoclax exerted synergistic in vitro lethality in the RT-DLBCL cells. Finally, as compared to each agent alone, combination therapy with BET-PROTAC and venetoclax significantly reduced lymphoma burden and improved survival of immune-depleted mice engrafted with CLR-RT-DLBCL. These findings highlight a novel, potentially effective therapy for RT-DLBCL.","journal":"Leukemia","year":2021,"id":169127,"datarank":0.5101796072493234,"base_score":3.4011973816621555,"endowment":3.4011973816621555,"self_citation_contribution":0.5101796072493234,"citation_network_contribution":0.0,"self_endowment_contribution":0.5101796072493234,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":29,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9543,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":304992,"name":"Christopher P. Mill","orcid":"0000-0003-0957-6009","position":1,"is_corresponding":false},{"id":304993,"name":"Dimuthu Perera","orcid":"0000-0002-4329-5676","position":2,"is_corresponding":false},{"id":572008,"name":"Christine Birdwell","orcid":null,"position":3,"is_corresponding":false},{"id":699416,"name":"Qing Deng","orcid":"0000-0001-5116-461X","position":4,"is_corresponding":false},{"id":255857,"name":"Haopeng Yang","orcid":"0000-0002-3870-2679","position":5,"is_corresponding":false},{"id":306482,"name":"Bernardo H Lara","orcid":null,"position":6,"is_corresponding":false},{"id":232850,"name":"Nitin Jain","orcid":"0000-0003-0114-8384","position":7,"is_corresponding":false},{"id":232849,"name":"Jan A. Burger","orcid":"0000-0002-6177-7572","position":8,"is_corresponding":false},{"id":232855,"name":"Alessandra Ferrajoli","orcid":"0000-0001-9547-4193","position":9,"is_corresponding":false},{"id":607910,"name":"John A. Davis","orcid":"0000-0002-5809-5976","position":10,"is_corresponding":false},{"id":304990,"name":"Dyana T. Saenz","orcid":"0000-0001-5935-977X","position":11,"is_corresponding":false},{"id":700055,"name":"Wendy Jin","orcid":null,"position":12,"is_corresponding":false},{"id":63736,"name":"Cristian Coarfa","orcid":"0000-0002-4183-4939","position":13,"is_corresponding":false},{"id":107240,"name":"Craig M. Crews","orcid":"0000-0002-8456-2005","position":14,"is_corresponding":false},{"id":17225,"name":"Michael R. Green","orcid":"0000-0001-6309-9472","position":15,"is_corresponding":false},{"id":304997,"name":"Joseph D. Khoury","orcid":"0000-0003-2621-3584","position":16,"is_corresponding":false},{"id":230407,"name":"Kapil N. Bhalla","orcid":"0000-0001-5209-5126","position":17,"is_corresponding":false},{"id":304991,"name":"Warren Fiskus","orcid":"0000-0002-7343-6214","position":0,"is_corresponding":true}],"reference_count":60,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:46:11.334362Z","pmid":"33654205","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":[]}