A FOXO1-dependent transcription network is a targetable vulnerability of mantle cell lymphomas
Ja-Young Jang, … , Hongwu Zheng, Jihye Paik
Ja-Young Jang, … , Hongwu Zheng, Jihye Paik
Published October 25, 2022
Citation Information: J Clin Invest. 2022;132(24):e160767. https://doi.org/10.1172/JCI160767.
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Research Article Oncology

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

Abstract

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.

Authors

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

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Figure 7

Pharmacological inhibition of FOXO1 suppresses MCL progression in vivo.

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Pharmacological inhibition of FOXO1 suppresses MCL progression in vivo. ...
(A) Experimental design of the in vivo treatment. (B) Bioluminescent imaging of CCMCL1 MCL recipient mice at the indicated day after initiation of treatment with cpd10 (100 mg/kg/d) or vehicle control. (C) Quantification of bioluminescent imaging responses to cpd10 treatment. Mean values of vehicle-treated (n = 5) and cpd10-treated (n = 6) mice are shown. Data represent mean ± SEM (n = 5 or 6). Results are representative of 2 independent experiments. Statistical analysis was performed using 2-tailed unpaired Student’s t test. ***P < 0.0005. (D) Kaplan-Meier survival curves of control and cpd10-treated mice. Statistical significance was determined using a log-rank test. (E) RT-qPCR analysis of indicated human genes in vehicle- and cpd10-treated spleens of CCMCL1 MCL recipient mice. Data represent mean ± SEM (n = 3 or 4). Results are representative of 2 independent experiments. Statistical analysis was performed using 2-tailed unpaired Student’s t test. **P < 0.005, ***P < 0.0005. (F) Predicted model of MCL lineage-survival transcriptional program and its dissolution following targeted inhibition of FOXO1.