{"doi":"10.1182/blood.2022019166","title":"Analysis and therapeutic targeting of the IL-1R pathway in anaplastic large cell lymphoma","abstract":"Anaplastic large cell lymphoma (ALCL), a subgroup of mature T-cell neoplasms with an aggressive clinical course, is characterized by elevated expression of CD30 and anaplastic cytology. To achieve a comprehensive understanding of the molecular characteristics of ALCL pathology and to identify therapeutic vulnerabilities, we applied genome-wide CRISPR library screenings to both anaplastic lymphoma kinase positive (ALK+) and primary cutaneous (pC) ALK- ALCLs and identified an unexpected role of the interleukin-1R (IL-1R) inflammatory pathway in supporting the viability of pC ALK- ALCL. Importantly, this pathway is activated by IL-1α in an autocrine manner, which is essential for the induction and maintenance of protumorigenic inflammatory responses in pC-ALCL cell lines and primary cases. Hyperactivation of the IL-1R pathway is promoted by the A20 loss-of-function mutation in the pC-ALCL lines we analyze and is regulated by the nonproteolytic protein ubiquitination network. Furthermore, the IL-1R pathway promotes JAK-STAT3 signaling activation in ALCLs lacking STAT3 gain-of-function mutation or ALK translocation and enhances the sensitivity of JAK inhibitors in these tumors in vitro and in vivo. Finally, the JAK2/IRAK1 dual inhibitor, pacritinib, exhibited strong activities against pC ALK- ALCL, where the IL-1R pathway is hyperactivated in the cell line and xenograft mouse model. Thus, our studies revealed critical insights into the essential roles of the IL-1R pathway in pC-ALCL and provided opportunities for developing novel therapeutic strategies.","journal":"Blood","year":2023,"id":371294,"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":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9618,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":889190,"name":"Wenjun Wu","orcid":"0000-0002-2528-4893","position":1,"is_corresponding":false},{"id":285274,"name":"Wei Wei","orcid":"0000-0002-6478-5973","position":2,"is_corresponding":false},{"id":271312,"name":"Wenming Xiao","orcid":"0000-0003-4096-9724","position":3,"is_corresponding":false},{"id":1131374,"name":"Michelle Lei","orcid":null,"position":4,"is_corresponding":false},{"id":241844,"name":"Kathy Q. Cai","orcid":"0000-0002-6034-3377","position":5,"is_corresponding":false},{"id":96765,"name":"Da Wei Huang","orcid":"0000-0002-6793-9966","position":6,"is_corresponding":false},{"id":1130907,"name":"Subin Jeong","orcid":"0000-0002-3333-0490","position":7,"is_corresponding":false},{"id":817840,"name":"Jing‐Ping Zhang","orcid":"0000-0003-0090-6710","position":8,"is_corresponding":false},{"id":243366,"name":"Hongbo Wang","orcid":"0000-0001-8530-2339","position":9,"is_corresponding":false},{"id":577118,"name":"Marshall E. Kadin","orcid":"0000-0003-1039-4384","position":10,"is_corresponding":false},{"id":238492,"name":"Thomas A. Waldmann","orcid":"0000-0003-4500-6660","position":11,"is_corresponding":false},{"id":35688,"name":"Louis M. Staudt","orcid":"0000-0002-1735-2892","position":12,"is_corresponding":false},{"id":670704,"name":"Masao Nakagawa","orcid":"0000-0002-8602-6054","position":13,"is_corresponding":false},{"id":407372,"name":"Yibin Yang","orcid":"0000-0002-9948-8696","position":14,"is_corresponding":false},{"id":408241,"name":"Zhihui Song","orcid":null,"position":0,"is_corresponding":true}],"reference_count":64,"raw_metadata":null,"created_at":"2026-07-19T01:15:45.330525Z","pmid":"37339580","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":[]}