The Journal of Clinical Investigation (Dec 2022)

A FOXO1-dependent transcription network is a targetable vulnerability of mantle cell lymphomas

  • Ja-Young Jang,
  • Inah Hwang,
  • Heng Pan,
  • Jun Yao,
  • Lapo Alinari,
  • Eddie Imada,
  • Claudio Zanettini,
  • Michael J. Kluk,
  • Yizhe Wang,
  • Yunkyoung Lee,
  • Hua V. Lin,
  • Xiangao Huang,
  • Maurizio Di Liberto,
  • Zhengming Chen,
  • Karla V. Ballman,
  • Lewis C. Cantley,
  • Luigi Marchionni,
  • Giorgio Inghirami,
  • Olivier Elemento,
  • Robert A. Baiocchi,
  • Selina Chen-Kiang,
  • Sandro Belvedere,
  • Hongwu Zheng,
  • Jihye Paik

Journal volume & issue
Vol. 132, no. 24

Abstract

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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.

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