Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Venetoclax resistance leads to broad resistance to standard-of-care anti-MM agents, but not to immunotherapies

ABSTRACT: Venetoclax is the first example of personalized medicine for multiple myeloma (MM), with meaningful clinical activity as a monotherapy and in combination in myeloma patients harboring the t(11:14) translocation. However, despite the high response rates and prolonged PFS, a significant proportion of patients eventually relapse. Here, we aimed to study adaptive molecular responses after the acquisition of venetoclax resistance in sensitive t(11:14) MM cell models. We therefore generated single-cell venetoclax-resistant t(11:14) MM cell lines and investigated the mechanisms contributing to resistance as well as the cells’ sensitivity to other treatments. Our data suggests that acquired resistance to venetoclax is characterized by reduced mitochondrial priming and changes in BCL-2 family proteins’ expression in MM cells, conferring broad resistance to standard-of-care anti-myeloma drugs. However, our results show that the resistant cells are still sensitive to immunotherapeutic treatments, highlighting the need to consider appropriate sequencing of these treatments following venetoclax-based regimens.

ORGANISM(S): Homo sapiens

PROVIDER: GSE269245 | GEO | 2024/06/06

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Venetoclax resistance leads to broad resistance to standard-of-care anti-MM agents, but not to immunotherapies

Project description:Venetoclax resistance leads to broad resistance to standard-of-care anti-MM agents, but not to immunotherapies

| PRJNA1120802 | ENA

Integrated Epigenetic and Transcriptional Single-Cell Analysis of t(11;14) Multiple Myeloma and Its BCL2 Dependency

Project description:This SuperSeries is composed of the SubSeries listed below. The translocation t(11;14) occurs in 20% of multiple myeloma (MM) patients and results in the upregulation of CCND1. Nearly two-thirds of t(11;14) MM cells are BCL2 primed and highly responsive to the oral BCL2 inhibitor venetoclax. While it is evident that this unique sensitivity to venetoclax depends on the BH3-proapoptotic protein priming of BCL2, the biology underlying t(11;14) MM dependency on BCL2 is poorly defined. Importantly, the epigenetic regulation of t(11;14) transcriptomes and its impact on gene regulation and clinical response to venetoclax remains elusive. In this study, by integrating ATACseq and RNAseq at the single-cell level in primary MM samples, we have defined the epigenetic regulome and transcriptome associated with t(11;14) MM. A "B cell-like" epigenetic signature was enriched in t(11;14) MM, confirming its phylogeny link to B cell rather than plasma cell biology. Of note, a loss of a "B cell-like" epigenetic signature with a gain of canonical plasma cell transcription factors was observed at the time of resistance to venetoclax. In addition, MCL1 and BCL2L1 copy number gains and structural rearrangements were linked to venetoclax resistance in t(11;14) MM patients. To date, this is the first study in which both scATAC-seq and scRNA-seq analysis are integrated into primary MM cells to obtain a deeper resolution of the epigenetic regulome and transcriptome associated with t(11;14) MM biology and venetoclax resistance.

2023-09-21 | GSE199373 | GEO

scCNVseq Datasets Supporting Integrated Epigenetic and Transcriptional Single-Cell Analysis of t(11;14) Multiple Myeloma and Its BCL2 Dependency

Project description:The translocation t(11;14) occurs in 20% of multiple myeloma (MM) patients and results in the upregulation of CCND1. Nearly two-thirds of t(11;14) MM cells are BCL2 primed and highly responsive to the oral BCL2 inhibitor venetoclax. While it is evident that this unique sensitivity to venetoclax depends on the BH3-proapoptotic protein priming of BCL2, the biology underlying t(11;14) MM dependency on BCL2 is poorly defined. Importantly, the epigenetic regulation of t(11;14) transcriptomes and its impact on gene regulation and clinical response to venetoclax remains elusive. In this study, by integrating ATACseq and RNAseq at the single-cell level in primary MM samples, we have defined the epigenetic regulome and transcriptome associated with t(11;14) MM. A "B cell-like" epigenetic signature was enriched in t(11;14) MM, confirming its phylogeny link to B cell rather than plasma cell biology. Of note, a loss of a "B cell-like" epigenetic signature with a gain of canonical plasma cell transcription factors was observed at the time of resistance to venetoclax. In addition, MCL1 and BCL2L1 copy number gains and structural rearrangements were linked to venetoclax resistance in t(11;14) MM patients. To date, this is the first study in which both scATAC-seq and scRNA-seq analysis are integrated into primary MM cells to obtain a deeper resolution of the epigenetic regulome and transcriptome associated with t(11;14) MM biology and venetoclax resistance.

2023-09-21 | GSE199372 | GEO

scATACseq Datasets Supporting Integrated Epigenetic and Transcriptional Single-Cell Analysis of t(11;14) Multiple Myeloma and Its BCL2 Dependency

2023-09-21 | GSE199268 | GEO

scRNAseq Datasets Supporting Integrated Epigenetic and Transcriptional Single-Cell Analysis of t(11;14) Multiple Myeloma and Its BCL2 Dependency

2023-09-21 | GSE199359 | GEO

“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

ETV4-Dependent Transcriptional Plasticity Maintains MYC Expression and Results in IMiD Resistance in Multiple Myeloma [RNA-seq]

Project description:Immunomodulatory Drugs (IMiDs) are a backbone therapy for multiple myeloma (MM). Despite their efficacy, most patients develop resistance and the mechanism(s) are not fully defined. Here, we show that IMiD responses are directed by IMiD-dependent degradation of IKZF1 and IKZF3 that bind to enhancers necessary to sustain the expression of MYC and other myeloma oncogenes. IMiD treatment universally depleted chromatin-bound IKZF1, but eviction of P300 and BRD4 co-activators only occurred in IMiD-sensitive cells. IKZF1-bound enhancers overlapped other transcription factor-binding motifs, including ETV4. ChIP-seq showed that ETV4 bound to the same enhancers as IKZF1, and ETV4 CRISPR/Cas9-mediated ablation resulted in sensitization of IMiD-resistant MM. ETV4 expression is associated with IMiD resistance in cell lines, poor prognosis in patients, and upregulated at relapse. These data indicate that ETV4 alleviates IKZF1 and IKZF3 dependency in MM by maintaining oncogenic enhancer activity and identify transcriptional plasticity as a previously unrecognized mechanism of IMiD resistance.

2023-10-30 | GSE246435 | GEO

ETV4-Dependent Transcriptional Plasticity Maintains MYC Expression and Results in IMiD Resistance in Multiple Myeloma [ChIP-seq]

2023-10-30 | GSE246429 | GEO

ETV4-Dependent Transcriptional Plasticity Maintains MYC Expression and Results in IMiD Resistance in Multiple Myeloma [ATAC-seq]

2023-10-30 | GSE246426 | GEO

Bouchnita2019 - A multiscale model to design therapeutic strategies that overcome drug resistance to tyrosine kinase inhibitors in multiple myeloma

Project description:Drug resistance (DR) is a phenomenon characterized by the tolerance of a disease to pharmaceutical treatment. In cancer patients, DR is one of the main challenges that limit the therapeutic potential of the existing treatments. Therefore, overcoming DR by restoring the sensitivity of cancer cells would be greatly beneficial. In this context, mathematical modeling can be used to provide novel therapeutic strategies that maximize the efficiency of anti-cancer agents and potentially overcome DR. In this paper, we present a new multiscale model devoted to the interaction of potential treatments with multiple myeloma (MM) development. In this model, MM cells are represented as individual objects that move, divide, and die by apoptosis. The fate of each cell depends on intracellular and extracellular regulation, as well as the administered treatment. The model is used to explore the combined effects of a tyrosine-kinase inhibitor (TKI) with a pentose phosphate pathway (PPP) inhibitor. We use numerical simulations to tailor effective and safe treatment regimens that may eradicate the MM tumors. The model suggests that an interval for the daily dose of the PPP inhibitor can maximize the responsiveness of MM cells to the treatment with TKIs. Then, it demonstrates that the combination of high-dose pulsatile TKI treatment with high-dose daily PPP inhibitor therapy can potentially eradicate the tumor.The predictions of numerical simulations using such a model can be considered as testable hypotheses in future pre-clinical experiments and clinical studies.

2020-01-09 | MODEL1912170004 | BioModels

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

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