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

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

PROVIDER: PRJNA757422 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15598800.fastq.gz	Fastqsanger.gz
	SRR15598801.fastq.gz	Fastqsanger.gz
	SRR15598802.fastq.gz	Fastqsanger.gz
	SRR15598803.fastq.gz	Fastqsanger.gz
	SRR15598804.fastq.gz	Fastqsanger.gz

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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]

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

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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.

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

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

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

Project description:ChIP-seq analysis of CCMCL1 MCL cells

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Targetable vulnerabilities in T- and NK-cell lymphomas identified through preclinical models

Project description:We report the expression profiles of 21 T- and NK-cell lymphomas to provide a platform for further investigation of targetable vulnerabilities in diseases represented by these cell lines

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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 [CUT&Run]

Project description:Rhabdomyosarcoma (RMS), a malignancy of impaired myogenic differentiation, is the most common soft tissue pediatric cancer. PAX3-FOXO1 oncofusions drive the majority of the clinically more aggressive fusion-positive rhabdomyosarcoma (FP-RMS). Recent studies have established an epigenetic basis for PAX3-FOXO1-driven oncogenic processes. However, details of PAX3-FOXO1 epigenetic mechanisms, including interactions with, and dependence on, other chromatin and transcription factors, are incompletely understood. We previously identified a novel disease-promoting epigenetic axis in RMS, involving the histone demethylase KDM3A and the ETS1 transcription factor, and demonstrated that this epigenetic axis interfaces with PAX3-FOXO1 both phenotypically and transcriptomically, including co-regulation of biological processes and genes important to FP-RMS progression. In this study, we demonstrate that KDM3A and ETS1 colocalize with PAX3-FOXO1 to enhancers of important disease-promoting genes in FP-RMS, including FGF8, IL4R, and MEST, as well as PODXL, which we define herein as a new FP-RMS-promoting gene. We show that ETS1, which is induced by both PAX3-FOXO1 and KDM3A, exists in complex with PAX3-FOXO1, and augments PAX3-FOXO1 chromatin occupancy. We further show that the PAX3-FOXO1/ETS1 complex can be disrupted by the clinically relevant small molecule inhibitor YK-4-279. YK-4-279 displaces PAX3-FOXO1 from chromatin and interferes with PAX3-FOXO1-dependent gene regulation, resulting in potent inhibition of growth and invasive properties in FP-RMS, along with downregulation of FGF8, IL4R, MEST and PODXL expression. We additionally show that, in some FP-RMS, KDM3A also increases PAX3-FOXO1 levels. Together, our studies illuminate mechanisms of action of the KDM3A/ETS1 regulatory module, and reveal novel targetable mechanisms of PAX3-FOXO1 chromatin complex regulation, in FP-RMS.

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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 [RNA-Seq]

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Project description:Chimeric transcription factors drive lineage-specific oncogenesis but are notoriously difficult to target. Alveolar rhabdomyosarcoma (RMS) is an aggressive childhood soft tissue sarcoma transformed by the pathognomonic PAX3–FOXO1 fusion protein, which governs a core regulatory circuitry transcription factor (CRC TF) network. Here we show that the histone lysine demethylase KDM4B is a therapeutic vulnerability for PAX3–FOXO1+ RMS. Genetic and pharmacologic inhibition of KDM4B significantly delays tumor growth by disrupting the expression of CRC TFs caused by epigenetic alterations of PAX3–FOXO1-governed super enhancers. Combining KDM4B inhibition with cytotoxic chemotherapy leads to significant tumor regression in preclinical PAX3–FOXO1+ RMS models. In summary, we have identified a targetable mechanism required for maintenance of PAX3-FOXO1-related CRC TF network, which may translate to a novel therapeutic approach for fusion-positive RMS.

2022-09-06 | GSE201224 | GEO

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