{"doi":"10.1002/hon.70094_384","title":"384 | PROGNOSTIC AND FUNCTIONAL IMPACT OF EGF‐JAK/STAT PATHWAY MUTATIONS IN ANGIOIMMUNOBLASTIC T‐CELL LYMPHOMA","abstract":"J. Lim equally contributing author. Introduction: Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive subtype of peripheral T-cell lymphoma (PTCL) with limited therapeutic options and poor prognosis. While mutations in epigenetic regulators and T-cell receptor (TCR) signaling genes are well characterized, the role of the epidermal growth factor (EGF)-Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway in AITL remains unclear. We investigated the prognostic and functional implications of EGF-JAK/STAT pathway mutations in AITL. Methods: Whole-exome sequencing and targeted deep sequencing were performed on two independent AITL cohorts: National Cancer Centre Singapore (NCCS, n = 137) and Atlas of Blood Cancer Genomes (ABCG, n = 118). Kaplan-Meier and Cox proportional hazard models were used to assess survival impact. Molecular dynamics (MD) simulations and immunohistochemistry (IHC) were conducted to characterize structural and expression changes in EGFR mutants. Functional validation was performed in 293T cells overexpressing wild-type and mutant EGFR (R803W, A864V). Western blot analysis was used to examine activation of downstream signaling pathways and response to EGFR inhibitors gefitinib and osimertinib. Results: EGF-JAK/STAT pathway mutations were identified in 20.3% (52/255) of AITL cases. EGFR was the only gene significantly associated with worse progression-free survival (PFS) in both NCCS and ABCG cohorts (p < 0.05). The recurrent EGFRR803W mutation was located in dominant tumor clones and was associated with elevated EGFR expression by IHC. MD simulations showed that R803W disrupted juxtamembrane (JM) interactions, leading to destabilization of the inactive conformation. In vitro, EGFRR803W and EGFRA864V enhanced phosphorylation of STAT5 compared to wild-type EGFR, supporting activation of the JAK/STAT pathway. Treatment with gefitinib and osimertinib inhibited STAT3 and extracellular signal-regulated kinase (ERK) phosphorylation, suggesting that EGFR mutations are targetable. Conclusions: EGFR mutations define a distinct subset of AITL with poor prognosis and aberrant activation of JAK/STAT signaling. Their presence in dominant tumor clones and their ability to activate oncogenic signaling suggest a driver role in AITL. The suppression of signaling by EGFR inhibitors supports the potential for targeted therapies in EGFR-mutant AITL. These findings highlight the importance of EGF-JAK/STAT pathway mutations as novel prognostic and therapeutic targets in AITL. Research funding declaration: The study was supported by grants from the NCCS Research Fund, Singapore Ministry of Health’s National Medical Research Council, Tanoto Foundation Professorship in Medical Oncology, New Century International Pte Ltd, and Ling Foundation. Keywords: genomics, epigenomics, and other -omics; aggressive T-cell non-Hodgkin lymphoma; diagnostic and prognostic biomarkers No potential sources of conflict of interest.","journal":"Hematological Oncology","year":2025,"id":568594,"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":0.9588,"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":1473463,"name":"Jing Quan Lim","orcid":"0000-0003-3732-8707","position":1,"is_corresponding":false},{"id":1473750,"name":"Leonardo P. A. Biral","orcid":null,"position":2,"is_corresponding":false},{"id":1473464,"name":"Chee Leong Cheng","orcid":"0000-0002-2140-4827","position":3,"is_corresponding":false},{"id":262968,"name":"Chandra Verma","orcid":"0000-0003-0733-9798","position":4,"is_corresponding":false},{"id":308700,"name":"Srinivasaraghavan Kannan","orcid":"0000-0002-9539-5249","position":5,"is_corresponding":false},{"id":1473751,"name":"Nur Ayuni Binte Muhammad Taib","orcid":null,"position":6,"is_corresponding":false},{"id":1473752,"name":"Beng Hooi Phang","orcid":null,"position":7,"is_corresponding":false},{"id":1473465,"name":"Kelila Xin Ye Chai","orcid":"0000-0003-2912-6451","position":8,"is_corresponding":false},{"id":1473753,"name":"Jhih-Yun Ho","orcid":null,"position":9,"is_corresponding":false},{"id":33053,"name":"Sandeep S. Davé","orcid":"0000-0003-4848-9768","position":10,"is_corresponding":false},{"id":286556,"name":"Jefferson Chan","orcid":"0000-0003-4139-4379","position":11,"is_corresponding":false},{"id":395713,"name":"Kikkeri N. Naresh","orcid":"0000-0003-3807-3638","position":12,"is_corresponding":false},{"id":1473754,"name":"S. T. Lim","orcid":null,"position":13,"is_corresponding":false},{"id":13889,"name":"Choon Kiat Ong","orcid":"0000-0001-6402-4288","position":14,"is_corresponding":false},{"id":109599,"name":"David C.S. Huang","orcid":"0000-0002-3101-4873","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:56:55.795846Z","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":[]}