Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Potent, p53-independent induction of NOXA sensitizes MLL-rearranged B-cell acute lymphoblastic leukemia cells to venetoclax [ATAC-Seq]

ABSTRACT: The prognosis for B cell precursor acute lymphoblastic leukemia patients with Mixed-Lineage Leukemia (MLL) gene rearrangements (MLLr BCP-ALL) is still extremely poor. Inhibition of anti-apoptotic protein BCL-2 with venetoclax emerged as a promising strategy for this subtype of BCP-ALL, however lack of sufficient responses in pre-clinical models and possibility of developing resistance exclude using venetoclax as monotherapy. Herein, we aimed to uncover potential mechanisms responsible for limited venetoclax activity in MLLr BCP-ALL and to identify drugs that could be used in combination therapy. Using RNA-seq, we observed that long-term exposure to venetoclax in vivo in patient derived xenograft model leads to downregulation of particular p53-related genes. Interestingly, addition of auranofin, a thioredoxin system inhibitor, sensitized MLLr BCP-ALL to venetoclax in various in vitro and in vivo models, independently on the p53 pathway functionality. Synergistic activity of these drugs resulted from auranofin-mediated upregulation of NOXA pro-apoptotic protein and potent induction of apoptotic cell death. More specifically, we observed that auranofin orchestrates upregulation of NOXA-encoding gene (PMAIP1) by chromatin remodeling and increased transcriptional accessibility. Altogether, these results present novel, promising drug combination that could be exploited for the treatment of MLLr BCP-ALL patients, including those with TP53 mutations.

ORGANISM(S): Homo sapiens

PROVIDER: GSE163228 | GEO | 2022/01/19

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Potent, p53-independent induction of NOXA sensitizes MLL-rearranged B-cell acute lymphoblastic leukemia cells to venetoclax [RNA-Seq]

Project description:The prognosis for B cell precursor acute lymphoblastic leukemia patients with Mixed-Lineage Leukemia (MLL) gene rearrangements (MLLr BCP-ALL) is still extremely poor. Inhibition of anti-apoptotic protein BCL-2 with venetoclax emerged as a promising strategy for this subtype of BCP-ALL, however lack of sufficient responses in pre-clinical models and possibility of developing resistance exclude using venetoclax as monotherapy. Herein, we aimed to uncover potential mechanisms responsible for limited venetoclax activity in MLLr BCP-ALL and to identify drugs that could be used in combination therapy. Using RNA-seq, we observed that long-term exposure to venetoclax in vivo in patient derived xenograft model leads to downregulation of particular p53-related genes. Interestingly, addition of auranofin, a thioredoxin system inhibitor, sensitized MLLr BCP-ALL to venetoclax in various in vitro and in vivo models, independently on the p53 pathway functionality. Synergistic activity of these drugs resulted from auranofin-mediated upregulation of NOXA pro-apoptotic protein and potent induction of apoptotic cell death. More specifically, we observed that auranofin orchestrates upregulation of NOXA-encoding gene (PMAIP1) by chromatin remodeling and increased transcriptional accessibility. Altogether, these results present novel, promising drug combination that could be exploited for the treatment of MLLr BCP-ALL patients, including those with TP53 mutations.

2022-01-19 | GSE163227 | GEO

ERAD inhibitors integrate ER stress with an epigenetic mechanism to activate BH3 only protein NOXA in cancer cells

Project description:The ubiquitin-proteasome system (UPS) has recently emerged as a major target for drug development in cancer therapy. The proteasome inhibitor bortezomib has clinical activity in multiple myeloma and mantle cell lymphoma. Here we report that Eeyarestatin I (EerI), a chemical inhibitor that blocks ER-associated protein degradation (ERAD), has anti-tumor and biologic activities similar to bortezomib, and can synergize with bortezomib. Like bortezomib, EerI-induced cytotoxicity requires the upregulation of the BH3 only pro-apoptotic protein NOXA. We further demonstrate that both EerI and bortezomib activate NOXA via an unanticipated mechanism that requires cooperation between two processes: First, these agents elicit an integrated stress response program at the ER to activate the CREB/ATF transcription factors ATF3 and ATF4. We show that ATF3 and ATF4 form a complex capable of binding to the NOXA promoter, which is required for NOXA activation. Second, EerI and bortezomib also block ubiquitination of histone H2A to relieve its inhibition on NOXA transcription. Our results identify a class of anti-cancer agents that integrate ER stress response with an epigenetic mechanism to induce cell death.

2009-02-20 | GSE14003 | GEO

Potent, p53-independent induction of NOXA sensitizes MLL-rearranged B-cell acute lymphoblastic leukemia cells to venetoclax

Project description:Potent, p53-independent induction of NOXA sensitizes MLL-rearranged B-cell acute lymphoblastic leukemia cells to venetoclax

| PRJNA685356 | ENA

Harnessing Noxa Demethylation to overcome Bortezomib resistance in Mantle Cell Lymphoma

Project description:Bortezomib (BZM) is the first proteasome inhibitor approved for relapsed Mantle Cell Lymphoma (MCL) with durable responses seen in 30%-50% of patients. The biological basis for differences in response to BZM is not completely understood. Our previous work demonstrated marked differences in methylation between primary MCL and normal B cells. We hypothesized that a subset of aberrantly methylated genes may be modulating BZM response in MCL patients. We examined genome-wide DNA methylation profiles in MCL patient treated with BZM using a NimbleGen array platform. DNA methylation analysis revealed a striking promoter hypomethylation in MCL patient samples following BZM treatment. Pathway analysis of differentially methylated genes identified molecular mechanisms of cancer as a top canonical pathway enriched among hypomethylated genes in BZM treated samples. Noxa, a pro-apoptotic Bcl-2 family member essential for the cytotoxicity of BZM, was significantly hypomethylated and induced following BZM treatment. Therapeutically, we could demethylate Noxa and induce anti-lymphoma activity using BZM and the DNA methytransferase inhibitor Decitabine (DAC) and their combination in vitro and in vivo in BZM resistant MCL cells. Noxa depletion by RNA interference protected MCL cells from death by these agents. These findings suggest a role for dynamic Noxa methylation for therapeutic benefit of BZM. Potent and synergistic cytotoxicity between BZM and DAC in vitro and in vivo supports a strategy for using epigenetic priming to overcome BZM resistance in relapsed MCL patients. Our data demonstrate that genomic methylation profiling can provide mechanistic insights to guide novel therapeutic approaches.

2017-02-09 | GSE58165 | GEO

Transcription profiling of human cell cancer line treated with bortezomib or Eeyarestatin I (EerI) reveals ERAD inhibitors integrate ER stress with an epigenetic mechanism to activate BH3 only protein NOXA in cancer cells

2009-02-28 | E-GEOD-14003 | biostudies-arrayexpress

Potent, p53-independent induction of NOXA sensitizes MLL-rearranged B-cell acute lymphoblastic leukemia cells to venetoclax [RNA-Seq]

Project description:Potent, p53-independent induction of NOXA sensitizes MLL-rearranged B-cell acute lymphoblastic leukemia cells to venetoclax [RNA-Seq]

| PRJNA685404 | ENA

Potent, p53-independent induction of NOXA sensitizes MLL-rearranged B-cell acute lymphoblastic leukemia cells to venetoclax [ATAC-Seq]

Project description:Potent, p53-independent induction of NOXA sensitizes MLL-rearranged B-cell acute lymphoblastic leukemia cells to venetoclax [ATAC-Seq]

| PRJNA685405 | ENA

Engineering ABT-737 Resistance in MYC-driven Lymphomas Identifies DHX9 as a Drug Response Modifier

Project description:Many traditional cytotoxic agents used in the treatment of cancer function by eliciting an apoptotic response in tumor cells. However, evasion of apoptosis by BCL-2 family members is often deregulated prior to therapeutic intervention leading to treatment failure. To address this, ABT-737 was rationally designed to target BCL-2-like family members and has shown promising results against tumor cells dependent on BCL-2 for their survival. One shortcoming is that MCL-1, a member of the BCL-2 family is poorly inhibited by ABT-737 and is a major cause of resistance. To gain insight into biological pathways that could circumvent this resistance, we designed an shRNA screen to identify novel sensitizers to ABT-737 by engineering MYC driven lymphomas that were resistant to ABT-737 due to endogenous MCL-1 expression. Utilizing this model, we performed a shRNA drop-out screen and identified Dhx9 as a target whose suppression sensitizes cells to ABT-737. DHX9 loss lead to replicative stress signaling, which in turn potently induced the BH3-only proteins, NOXA and PUMA, in a p53-dependent manner to curtail MCL-1 activity. Induction of NOXA is essential for ABT-737 sensitization. Our results ascribe a novel role for DHX9 in the replicative stress pathway and link DHX9 activity to p53 function in vivo. Comparison of Arf-/-Eu-myc/Bcl-2 lymphomas expressing either control Rluc.713 or Dhx9 shRNA, Dhx9.1241

2013-04-03 | E-GEOD-36938 | biostudies-arrayexpress

NOXA and RUNX1 in PDAC

Project description:NOXA expression drives synthetic lethality to RUNX1 inhibition in pancreatic cancer

| PRJEB39828 | ENA

“Direct to Drug” screening as a precision medicine tool in multiple myeloma

Project description:Seventy-six FDA approved oncology drugs and emerging therapeutics were evaluated in 25 multiple myeloma (MM) and 15 non-Hodgkin’s lymphoma cell lines and in 113 primary MM samples. Ex vivo drug sensitivities were mined for associations with clinical phenotype, cytogenetic, genetic mutation and transcriptional profiles. We investigated the predictive value of anti-apoptotic BCL2 family member transcriptomic ratios as biomarkers of venetoclax sensitivity. RNA-seq analysis was available in 38 primary patient samples, from which we identified the 9 most (median AUC 0.09409) and least (median AUC 0.7195) sensitive samples to venetoclax.

2020-05-22 | GSE148715 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data