biostudies-literatureJang JYForkhead BioTherapeuticsNCI/NIHNCI NIH HHSNational Research Foundation of KoreaLeukemia and Lymphoma Societye160767https://www.ebi.ac.uk/biostudies/studies/S-EPMC9753996biostudies-literatureUnknown132(24)Targeting lineage-defined transcriptional dependencies has emerged as an effective therapeutic strategy in cancer treatment. Through screening for molecular vulnerabilities of mantle cell lymphoma (MCL), we identified a set of transcription factors (TFs) including FOXO1, EBF1, PAX5, and IRF4 that are essential for MCL propagation. Integrated chromatin immunoprecipitation and sequencing (ChIP-Seq) with transcriptional network reconstruction analysis revealed FOXO1 as a master regulator that acts upstream in the regulatory TF hierarchy. FOXO1 is both necessary and sufficient to drive MCL lineage commitment through supporting the lineage-specific transcription programs. We further show that FOXO1, but not its close paralog FOXO3, can reprogram myeloid leukemia cells and induce B-lineage gene The Journal of clinical investigationA FOXO1-dependent transcription network is a targetable vulnerability of mantle cell lymphomas.PMC9753996201077P30 CA016058MCL7001–182021R1A6A3A03039136P01 CA214274CA214274Yao JElemento OKluk MJBelvedere SBaiocchi RAJang JYHwang IDi Liberto MPan HZanettini CImada EZheng HChen ZBallman KVPaik JLin HVHuang XCantley LCChen-Kiang SMarchionni LAlinari LLee YWang YInghirami GfalseA FOXO1-dependent transcription network is a targetable vulnerability of mantle cell lymphomas.Targeting lineage-defined transcriptional dependencies has emerged as an effective therapeutic strategy in cancer treatment. Through screening for molecular vulnerabilities of mantle cell lymphoma (MCL), we identified a set of transcription factors (TFs) including FOXO1, EBF1, PAX5, and IRF4 that are essential for MCL propagation. Integrated chromatin immunoprecipitation and sequencing (ChIP-Seq) with transcriptional network reconstruction analysis revealed FOXO1 as a master regulator that acts upstream in the regulatory TF hierarchy. FOXO1 is both necessary and sufficient to drive MCL lineage commitment through supporting the lineage-specific transcription programs. We further show that FOXO1, but not its close paralog FOXO3, can reprogram myeloid leukemia cells and induce B-lineage gene 2022-01-01T00:00:00Z2022 Dec2026-05-29T18:57:57.964Z2025-04-19T22:45:43.484ZS-EPMC97539963628257210.1172/JCI160767