|A FOXO1-dependent transcription network is a targetable vulnerability of mantle cell lymphomas.
|Year of Publication
|Jang J-Y, Hwang I, Pan H, Yao J, Alinari L, Imada E, Zanettini C, Kluk MJ, Wang Y, Lee Y, Lin HV, Huang X, Di Liberto M, Chen Z, Ballman KV, Cantley LC, Marchionni L, Inghirami G, Elemento O, Baiocchi RA, Chen-Kiang S, Belvedere S, Zheng H, Paik J
|J Clin Invest
|2022 Dec 15
|Adult, Forkhead Box Protein O1, Gene Regulatory Networks, Humans, Lymphoma, Mantle-Cell
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 expression. Finally, we demonstrate that cpd10, a small molecule identified from an enriched FOXO1 inhibitor library, induces a robust cytotoxic response in MCL cells in vitro and suppresses MCL progression in vivo. Our findings establish FOXO1 inhibition as a therapeutic strategy targeting lineage-driven transcriptional addiction in MCL.
|J Clin Invest
Luigi Marchionni, M.D., Ph.D. Giorgio Inghirami, M.D. Selina Chen-Kiang, Ph.D. Ji-Hye Paik, Ph.D.