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Efficacy of BET protein proteolysis targeted chimera-based combinations against novel patient-derived models of Richter Transformation-Diffuse Large B-Cell Lymphoma [RNA-Seq]

ABSTRACT: Efficacy of BET protein proteolysis targeted chimera-based combinations against novel patient-derived models of Richter Transformation-Diffuse Large B-Cell Lymphoma [RNA-Seq]

PROVIDER: PRJNA646385 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12225065_1.fastq.gz	Fastqsanger.gz
	SRR12225065_2.fastq.gz	Fastqsanger.gz
	SRR12225066_1.fastq.gz	Fastqsanger.gz
	SRR12225066_2.fastq.gz	Fastqsanger.gz
	SRR12225067_1.fastq.gz	Fastqsanger.gz

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Efficacy of BET protein proteolysis targeted chimera-based combinations against novel patient-derived models of Richter Transformation-Diffuse Large B-Cell Lymphoma

Project description:Efficacy of BET protein proteolysis targeted chimera-based combinations against novel patient-derived models of Richter Transformation-Diffuse Large B-Cell Lymphoma

| PRJNA646378 | ENA

Efficacy of BET protein proteolysis targeted chimera-based combinations against novel patient-derived models of Richter Transformation-Diffuse Large B-Cell Lymphoma [ATAC-Seq]

Project description:Efficacy of BET protein proteolysis targeted chimera-based combinations against novel patient-derived models of Richter Transformation-Diffuse Large B-Cell Lymphoma [ATAC-Seq]

| PRJNA646373 | ENA

Efficacy of BET protein proteolysis targeted chimera-based combinations against novel patient-derived models of Richter Transformation-Diffuse Large B-Cell Lymphoma [ChIP-Seq]

Project description:Efficacy of BET protein proteolysis targeted chimera-based combinations against novel patient-derived models of Richter Transformation-Diffuse Large B-Cell Lymphoma [ChIP-Seq]

| PRJNA646372 | ENA

BET proteolysis targeted chimera-based therapy of novel models of Richter Transformation-diffuse large B-cell lymphoma.

Project description:Richter Transformation (RT) develops in CLL as an aggressive, therapy-resistant, diffuse large B cell lymphoma (RT-DLBCL), commonly clonally-related (CLR) to the concomitant CLL. Lack of available pre-clinical human models has hampered the development of novel therapies for RT-DLBCL. Here, we report the profiles of genetic alterations, chromatin accessibility and active enhancers, gene-expressions and anti-lymphoma drug-sensitivity of three newly established, patient-derived, xenograft (PDX) models of RT-DLBCLs, including CLR and clonally-unrelated (CLUR) to concomitant CLL. The CLR and CLUR RT-DLBCL cells display active enhancers, higher single-cell RNA-Seq-determined mRNA, and protein expressions of IRF4, TCF4, and BCL2, as well as increased sensitivity to BET protein inhibitors. CRISPR knockout of IRF4 attenuated c-Myc levels and increased sensitivity to a BET protein inhibitor. Co-treatment with BET inhibitor or BET-PROTAC and ibrutinib or venetoclax exerted synergistic in vitro lethality in the RT-DLBCL cells. Finally, as compared to each agent alone, combination therapy with BET-PROTAC and venetoclax significantly reduced lymphoma burden and improved survival of immune-depleted mice engrafted with CLR-RT-DLBCL. These findings highlight a novel, potentially effective therapy for RT-DLBCL.

| S-EPMC8410602 | biostudies-literature

Efficacy of BET protein proteolysis targeted chimera-based combinations against novel patient-derived models of Richter Transformation-Diffuse Large B-Cell Lymphoma [RNA-Seq]

Project description:RichterTransformation (RT) develops in CLL as an aggressive, therapy resistant diffuse large B cell lymphoma (RT-DLBCL), commonly clonally related (CLR) to the antecedent CLL. Lack of available pre-clinical models has hampered development of novel therapies for RT-DLBCL. Here,we report the profiles of genetic alterations, active enhancers, gene-expressions and anti-lymphoma drug-sensitivity patterns of first-ever established, patient-derived xenograft models of RT-DLBCLs, including CLR and clonally unrelated (CLUR) to antecedent CLL. The CLR and CLUR RT-DLBCL cells display active enhancers, higher single-cell RNA-Seq-determined mRNA, and protein-expressions of IRF4, TCF4 and BCL2. This correlated with higher sensitivity to BET inhibitor and BET-PROTAC-based combinations with ibrutinib or venetoclax, including improved in vivo tumor burden and survival in the PDX model of CLR-RT-DLBCL.

2021-08-26 | GSE154462 | GEO

Efficacy of BET protein proteolysis targeted chimera-based combinations against novel patient-derived models of Richter Transformation-Diffuse Large B-Cell Lymphoma [ChIP-Seq]

2021-08-26 | GSE154457 | GEO

Efficacy of BET protein proteolysis targeted chimera-based combinations against novel patient-derived models of Richter Transformation-Diffuse Large B-Cell Lymphoma [ATAC-Seq]

2021-08-26 | GSE154456 | GEO

Efficacy of BET protein proteolysis targeted chimera-based combinations against novel patient-derived models of Richter Transformation-Diffuse Large B-Cell Lymphoma

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

2021-08-26 | GSE154463 | GEO

RUNX1 knockdown and BET protein proteolysis targeting chimera (PROTAC) exerts potent lethal activity against mtRUNX1 AML cells

Project description:Bromodomain extraterminal protein (BETP) inhibitors transcriptionally repress oncoproteins which undermines the growth and survival of AML cells. However, BETi treatment causes accumulation of BETPs, associated with reversible binding and incomplete inhibition of BRD4, which potentially compromises the activity of BETi in AML cells. Unlike BETi, BET-PROTAC (proteolysis-targeting chimera) ARV-825 recruits and utilize an E3-ubiquitin ligase to effectively degrade BETPs in AML cells. BET-PROTACs induce more apoptosis than BETi of mtRUNX1 AML cells. BET-PROTAC treatment induced more perturbations in the mRNA and protein expressions than BETi. It was noted that treatment with BETi or BET-PROTAC caused significant and sustained depletion of RUNX1 in AML cells. We also determined the effects of global depletion of RUNX1 in mtRUNX1 expressing AML OCI-AML5 cells. We observed an overlap in the signature of RUNX1 knockdown by shRNA with that of OTX015 and ARV-825 in OCI-AML5 cells.

2020-08-11 | GSE119261 | GEO

Novel BET protein Proteolysis Targeting Chimera (BET-PROTAC) exerts superior lethal activity than Bromodomain Inhibitor (BETi) against post-myeloproliferative Neoplasm (MPN) Secondary (s) AML Cells

Project description:The PROTAC (proteolysis-targeting chimera) ARV-825 recruits bromodomain and extraterminal (BET) proteins to the E3 ubiquitin ligase cereblon, leading to degradation of BET proteins, including BRD4. Whereas the BET-protein inhibitor (BETi) OTX015 caused accumulation of BRD4, treatment with equimolar concentrations of ARV-825 caused sustained and profound depletion (>90%) of BRD4 and induced significantly more apoptosis in cultured and patient-derived (PD) CD34+ post-MPN sAML cells, while relatively sparing the CD34+ normal hematopoietic progenitor cells. RNA-Seq, Reversed Phase Protein Array and mass cytometry ‘CyTOF’ analyses demonstrated that ARV-825 caused greater perturbations in mRNA and protein expressions than OTX015 in sAML cells. Specifically, compared to OTX015, ARV-825 treatment caused more robust and sustained depletion of c-Myc, CDK4/6, JAK2, pSTAT3/5, PIM1 and Bcl-xL, while increasing the levels of p21 and p27. Compared to OTX015, PROTAC ARV-771 treatment caused greater reduction in leukemia burden and further improved survival of NSG mice engrafted with luciferase-expressing HEL92.1.7 cells. Co-treatment with ARV-825 and JAK inhibitor ruxolitinib was synergistically lethal against the established and PD-CD34+ sAML cells. Notably, ARV-825 induced high levels of apoptosis in the in vitro generated ruxolitinib-persister or ruxolitinib-resistant sAML cells. These findings strongly support the in vivo testing of the BRD4-PROTAC based combinations against post-MPN sAML.

2017-04-06 | GSE93578 | GEO

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