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Updated: Aug 24, 2025
Mapping the Structure-Function Relationships of Disordered Oncogenic Transcription Factors Using Transcriptomic Analysis
Published on: June 27, 2020
A FOXO1-dependent transcription network is a targetable vulnerability of mantle cell lymphomas
Ja-Young Jang1, Inah Hwang1, Heng Pan2
1Department of Pathology and Laboratory Medicine and.
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.
Insights
FOXO1 is a master regulator essential for mantle cell lymphoma (MCL) propagation. Inhibiting FOXO1 with a novel compound shows promise as a targeted therapy for MCL, demonstrating efficacy both in vitro and in vivo.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Targeting lineage-specific transcriptional dependencies is a key strategy in cancer therapy.
- Mantle cell lymphoma (MCL) is a B-cell malignancy with specific molecular vulnerabilities.
- Transcription factors (TFs) play crucial roles in cancer cell propagation.
Purpose of the Study:
- To identify molecular vulnerabilities in MCL.
- To elucidate the role of transcription factors in MCL pathogenesis.
- To evaluate FOXO1 as a therapeutic target in MCL.
Main Methods:
- Screening for molecular vulnerabilities in MCL.
- Integrated chromatin immunoprecipitation and sequencing (ChIP-Seq) and transcriptional network reconstruction.
- In vitro and in vivo studies using a FOXO1 inhibitor (cpd10).
Main Results:
- Identified FOXO1, EBF1, PAX5, and IRF4 as essential TFs for MCL.
- FOXO1 identified as a master regulator driving MCL lineage commitment.
- FOXO1 can reprogram myeloid leukemia cells to express B-lineage genes.
- cpd10 demonstrated potent cytotoxic effects on MCL cells and suppressed tumor growth in vivo.
Conclusions:
- FOXO1 is a critical regulator of MCL lineage and essential for its propagation.
- FOXO1 inhibition represents a promising therapeutic strategy for MCL.
- Targeting lineage-driven transcriptional addiction offers a novel approach for cancer treatment.
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