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MYC dependency in GLS1 and NAMPT is a therapeutic vulnerability in multiple myeloma

ABSTRACT: MYC dependency in GLS1 and NAMPT is a therapeutic vulnerability in multiple myeloma

PROVIDER: PRJNA1010798 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25814708_1.fastq.gz	Fastqsanger.gz
	SRR25814708_2.fastq.gz	Fastqsanger.gz
	SRR25814709_1.fastq.gz	Fastqsanger.gz
	SRR25814709_2.fastq.gz	Fastqsanger.gz
	SRR25814710_1.fastq.gz	Fastqsanger.gz

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MYC dependency in GLS1 and NAMPT is a therapeutic vulnerability in multiple myeloma

Project description:Multiple myeloma is an incurable hematological malignancy evolving from precursor states to advanced phases of the disease. MYC abnormalities play a critical role in the disease progression. Nevertheless, MYC lacks therapeutic drugability, thereby necessitating the exploration of alternative strategies aimed at circumventing the challenges associated with targeting MYC. In this study, we hypothesized that MYC upregulation induces genomic dependencies in tumor cells, creating vulnerabilities that can be exploited therapeutically. We discovered a differential dependency on glutamine metabolism in MYC overexpressing cells. We functionally explored these dependencies as a selective targetable vulnerability in vitro and in vivo. Furthermore, we uncovered a potential synergistic combination that can exacerbated this metabolic vulnerability, Collectively, our in vitro and in vivo results revealed an effective therapeutic combinatory strategy in the context of MYC overexpressing MM.

2024-04-09 | PXD050010 | Pride

MYC dependency in GLS1 and NAMPT is a therapeutic vulnerability in multiple myeloma

Project description:Multiple myeloma is an incurable hematological malignancy evolving from precursor states to advanced phases of the disease. MYC abnormalities play a critical role in the disease progression. Nevertheless, MYC lacks therapeutic drugability, thereby necessitating the exploration of alternative strategies aimed at circumventing the challenges associated with targeting MYC. In this study, we hypothesized that MYC upregulation induces genomic dependencies in tumor cells, creating vulnerabilities that can be exploited therapeutically. We discovered a differential dependency on glutamine metabolism in MYC overexpressing cells. We functionally explored these dependencies as a selective targetable vulnerability in vitro and in vivo. Furthermore, we uncovered a potential synergistic combinations that can exacerbated this metabolic vulnerability, Collectively, our in vitro and in vivo results revealed an effective therapeutic combinatory strategy in the context of MYC overexpressing MM.

2023-09-04 | GSE241948 | GEO

MYC dependency in GLS1 and NAMPT is a therapeutic vulnerability in multiple myeloma.

Project description:Multiple myeloma (MM) is an incurable hematological malignancy in which MYC alterations contribute to the malignant phenotype. Nevertheless, MYC lacks therapeutic druggability. Here, we leveraged large-scale loss-of-function screens and conducted a small molecule screen to identify genes and pathways with enhanced essentiality correlated with MYC expression. We reported a specific gene dependency in glutaminase (GLS1), essential for the viability and proliferation of MYC overexpressing cells. Conversely, the analysis of isogenic models, as well as cell lines dataset (CCLE) and patient datasets, revealed GLS1 as a non-oncogenic dependency in MYC-driven cells. We functionally delineated the differential modulation of glutamine to maintain mitochondrial function and cellular biosynthesis in MYC overexpressing cells. Furthermore, we observed that pharmaceutical inhibition of NAMPT selectively affects MYC upregulated cells. We demonstrate the effectiveness of combining GLS1 and NAMPT inhibitors, suggesting that targeting glutaminolysis and NAD synthesis may be a promising strategy to target MYC-driven MM.

| S-EPMC10952034 | biostudies-literature

Molecular sequelae of Nampt Inhibition in Human Multiple Myeloma cell line

Project description:Evaluation of specific coordinated pattern of transcriptional events consistent with anti-myeloma activity of FK866 (chemical Nampt inhibitor)

2012-11-05 | GSE35414 | GEO

Molecular sequelae of Nampt Inhibition in Human Multiple Myeloma cell line

Project description:Evaluation of specific coordinated pattern of transcriptional events consistent with anti-myeloma activity of FK866 (chemical Nampt inhibitor) 3 samples were analyzed using as control the untreated cells. Treated cells were cultured in presence of FK866 at concentration of 10nM for 6 and 24 hours.

2012-11-05 | E-GEOD-35414 | biostudies-arrayexpress

MFF marks a metabolic vulnerability of multiple myeloma

Project description:MFF marks a metabolic vulnerability of multiple myeloma

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GLS1 governs vascular smooth muscle cell phenotypic switching and aortic dissection via glutamate metabolism

Project description:To evaluate the roles of glutaminase 1 (GLS1) in vascular smooth muscle cells (VSMCs) phenotypic switching and aortic dissection (AD). Integrative transcriptomic analyses were performed to identify the candidate genes involved in VSMC phenotypic switching in AD. The expression of GLS1 in VSMCs was assessed by qRT-PCR, Western blot and immunofluorescence. RNA-sequencing analysis was performed to recapitulate possible changes in the transcriptome profile of GLS1 in VSMCs. We identified GLS1 as a potential regulator in AD. GLS1 expression was significantly downregulated in VSMCs from both human AD aortic tissues and mouse models. Mechanistically, down-regulation of GLS1 impaired glutamate metabolism, leading to reduced levels of glutathione and α-ketoglutarate, thereby promoting mitochondrial dysfunction and accumulation of reactive oxygen species, which activated the PI3K/AKT pathway and ultimately triggered VSMC phenotypic switching. These findings revealed a critical role of GLS1-mediated glutamate metabolism in VSMC phenotypic switching and suggest a promising therapeutic target for AD.

2026-03-20 | GSE324926 | GEO

Transcriptional profiling for CRISPR activation of a myeloma-preferential dependency

Project description:Clinical progress in multiple myeloma (MM), an incurable plasma cell (PC) neoplasia, has been driven by therapies which have limited applications beyond MM/PC neoplasias and do not target specific oncogenic mutations in MM. Instead, these agents target pathways critical for PC biology yet largely dispensable for malignant or normal cells of most other lineages. We systematically characterized the lineage-preferential molecular dependencies of MM through genome-scale CRISPR gene editing studies in MM vs. hundreds of non-MM lines. This identified a collection of genes whose disruption has more pronounced or recurrent impact on the MM cell fitness compared to other malignancies. These genes, some known, others not previously linked to MM, encode transcription factors, chromatin modifiers, endoplasmic reticulum components, metabolic regulators or signaling molecules. The current dataset describes the transcriptional profiling of a MM cell line with CRISPR activation for the myeloma-preferential dependency, POU2AF1. The transcriptional profile of CRISPR activation of an additional gene (PANK1), which does not serve as a MM-preferential dependency in CRISPR gene editing studies, is also described.

2023-03-21 | GSE186997 | GEO

scRNAseq analysis of kidney treated with GLS1 inhibitor [scRNA-seq Kid_BPTES]

Project description:We employed the Chromium GEM-X single-cell RNA sequencing platform by 10x Genomics to investigate the effects of the GLS1 inhibitor, BPTES, on the kidney single-cell transcriptome of 19- to 20-month-old wild-type male mice. Previous studies have identified GLS1 as a potential senolytic reagent capable of eliminating senescent cells. Our aim was to determine which cell populations are selectively removed by GLS1 inhibition in aged mice and to assess how this intervention alters intercellular interactions across different cell types.

2025-07-02 | GSE301292 | GEO

scRNAseq analysis of lung treated with GLS1 inhibitor [scRNA-seq Lung_BPTES]

Project description:We employed the Chromium GEM-X single-cell RNA sequencing platform by 10x Genomics to investigate the effects of the GLS1 inhibitor, BPTES, on the lung single-cell transcriptome of 19- to 20-month-old wild-type male mice. Previous studies have identified GLS1 as a potential senolytic reagent capable of eliminating senescent cells. Our aim was to determine which cell populations are selectively removed by GLS1 inhibition in aged mice and to assess how this intervention alters intercellular interactions across different cell types.

2025-07-02 | GSE300532 | GEO

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