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FOXO1 dependent transcription network is a targetable vulnerability of Mantle Cell Lymphomas

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE182689 | GEO | 2023/05/25

REPOSITORIES: GEO

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

Project description: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.

| S-EPMC9753996 | biostudies-literature

FOXO1 dependent transcription network is a targetable vulnerability of Mantle Cell Lymphomas [ChIP-Seq]

Project description:ChIP-seq analysis of CCMCL1 MCL cells

2023-05-25 | GSE182687 | GEO

FOXO1 dependent transcription network is a targetable vulnerability of Mantle Cell Lymphomas [RNA-Seq]

Project description:RNA_seq analysis for FOXO1 depleted MCL cells

2023-05-25 | GSE182688 | GEO

FOXO1 dependent transcription network is a targetable vulnerability of Mantle Cell Lymphomas

Project description:FOXO1 dependent transcription network is a targetable vulnerability of Mantle Cell Lymphomas

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FOXO1 dependent transcription network is a targetable vulnerability of Mantle Cell Lymphomas [ChIP-Seq]

Project description:FOXO1 dependent transcription network is a targetable vulnerability of Mantle Cell Lymphomas [ChIP-Seq]

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FOXO1 dependent transcription network is a targetable vulnerability of Mantle Cell Lymphomas [RNA-Seq]

Project description:FOXO1 dependent transcription network is a targetable vulnerability of Mantle Cell Lymphomas [RNA-Seq]

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Dependence of PAX3-FOXO1 chromatin occupancy on ETS1 at important disease-promoting genes exposes new targetable vulnerability in Fusion-Positive Rhabdomyosarcoma

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-10-25 | GSE279337 | GEO

Defective transcription elongation in human cancers imposes targetable proteotoxic vulnerability.

Project description:Successful cancer therapy is contingent on identifying cancer-specific aberrant phenotypes and their associated vulnerabilities. We recently reported that a subset of almost every cancer type contains a genome-wide defect in RNA Polymerase II-mediated transcription elongation (TEdef), which impairs the expression of long genes and confers resistance to anti-tumor immune attack. Using a combination of computational analysis and laboratory experiments, we report that tumor cells with TEdef have widespread overexpression of the components of the protein homeostasis machinery (mostly composed of short genes), including protein folding and clearance. Accordingly, TEdef cells were characterized by abnormally high levels of insoluble protein aggregates in the cytoplasm and autophagy influx. We present evidence that TEdef cells exhibit impaired clearance of misfolded protein aggregates through the ubiquitin-proteasome system, and thus rely on autophagy for their degradation. As such, while these cells were highly resistant to proteasome inhibitors, they were acutely sensitive to inhibitors of autophagy in vitro and in vivo. This study reveals a major aberrant phenotype that is observed in ∼15-25% of all cancers and characterizes a unique cellular vulnerability that can be readily exploited in the clinic to improve treatment efficacy.

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Targeting KDM4B to disrupt the core regulatory transcription network governed by PAX3-FOXO1 in high-risk rhabdomyosarcoma

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-09-06 | GSE157095 | GEO

Deficiency of TET2-mediated KMT2D self-transcription confers a targetable vulnerability in hepatocellular carcinoma.

Project description:Hepatocellular carcinoma (HCC) has become a leading cause of cancer-related mortality worldwide. Conventional therapies tend to exacerbate comorbidities, liver dysfunction, and relapse, rendering an urgent demand for novel strategy for management of HCC. Here, we reported that DNA dioxygenase TET2 collaborates with histone methyltransferase KMT2D to enable transcription of KMT2D and ARID1A in HCC. Mechanistically, KMT2D and ARID1A are the major epigenetic targets of TET2 through RNA-seq analysis. Moreover, KMT2D recruits TET2 to facilitate self-transcription via oxidation of 5-methylcytosine in promoter, thereby maintaining expression of ARID1A. Physiologically, KMT2D was identified as a tumor suppressor and mediates the antitumor effect of vitamin C in HCC. Tumors with depleted KMT2D present growth advantage over control group. Vitamin C is able to impair tumor growth, which is compromised by deficiency of KMT2D. Furthermore, loss of KMT2D sensitizes HCC tumors to cisplatin with reduced tumor weight and high level of DNA damage. Ultimately, TET2-KMT2D axis correlates with prognosis of patients with HCC. Patients with high amounts of TET2 and KMT2D present better outcome. Our findings not only put forth a heretofore unrecognized mechanism underlying cross-talk between TET2 and KMT2D in mediating self-transcription of KMT2D, but also propose a targetable vulnerability for HCC therapy on the basis of TET2-KMT2D axis.

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