Targeting DNA2 Overcomes Metabolic Reprogramming in Multiple Myeloma
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE196766 | GEO | 2023/11/27
REPOSITORIES: GEO
Similar Datasets
Project description:Targeting DNA2 Overcomes Metabolic Reprogramming in Multiple Myeloma
| PRJNA807285 | ENA
Project description:DNA damage resistance is a major barrier to effective DNA-damaging therapy in multiple myeloma (MM). To discover mechanisms through which MM cells overcome DNA damage, we investigate how MM cells become resistant to antisense oligonucleotide (ASO) therapy targeting Interleukin enhancer binding factor 2 (ILF2), a DNA damage regulator that is overexpressed in 70% of MM patients whose disease has progressed after standard therapies have failed. Here, we show that MM cells undergo adaptive metabolic rewiring to restore energy balance and promote survival in response to DNA damage activation. Using a CRISPR/Cas9 screening strategy, we identify the mitochondrial DNA repair protein DNA2, whose loss of function suppresses MM cells' ability to overcome ILF2 ASO-induced DNA damage, as being essential to counteracting oxidative DNA damage. Our study reveals a mechanism of vulnerability of MM cells that have an increased demand for mitochondrial metabolism upon DNA damage activation.
| S-EPMC10853245 | biostudies-literature
Project description:SUMOylation, a posttranslational modification, regulates proteins by covalent attachment of small ubiquitin-like modifier (SUMO) proteins to a lysine (Lys) residue on target proteins. Here we use TAK-981, a selective SUMO-activating enzyme (SAE) inhibitor, to inhibit global SUMOylation in glucocorticoid sensitive and resistant multiple myeloma cell lines.
2021-12-31 | GSE163682 | GEO
Project description:Multiple myeloma (MM) drug resistance highlights a need for alternative therapeutic strategies. In this study, we show that CASIN, a selective inhibitor of cell division cycle 42 (Cdc42) GTPase, inhibited proliferation and survival of melphalan/bortezomib-resistant MM cells more profoundly than that of the sensitive cells. Furthermore, CASIN was more potent than melphalan/bortezomib in inhibiting melphalan/bortezomib-resistant cells. In addition, CASIN sensitized melphalan/bortezomib-resistant cells to this drug combination. Mechanistically, Cdc42 activity was higher in melphalan/bortezomib-resistant cells than that in the sensitive cells. CASIN inhibited mono-ubiquitination of Fanconi anemia (FA) complementation group D2 (FANCD2) of the FA DNA damage repair pathway in melphalan-resistant but not melphalan-sensitive cells, thereby sensitizing melphalan-resistant cells to DNA damage. CASIN suppressed epidermal growth factor receptor (EGFR), signal transducer and activator of transcription 3 (STAT3), and extracellular signal-regulated kinase (ERK) activities to a larger extent in bortezomib-resistant than in melphalan-sensitive cells. Reconstitution of ERK activity partially protected CASIN-treated bortezomib-resistant cells from death, suggesting that CASIN-induced killing is attributable to suppression of ERK. Importantly, CASIN extended the lifespan of mouse xenografts of bortezomib-resistant cells and caused apoptosis of myeloma cells from bortezomib-resistant MM patients. Finally, CASIN had negligible side effects on peripheral blood mononuclear cells (PBMC) from healthy human subjects and normal B cells. Our data provide a proof of concept demonstration that rational targeting of Cdc42 represents a promising approach to overcome MM drug resistance.
| S-EPMC6779689 | biostudies-literature
Project description:Mechanisms of constitutive NF-kappaB signaling in multiple myeloma are unknown. An inhibitor of IkappaB kinase beta (IKKbeta), targeting the classical NF-kappaB pathway, was lethal to many myeloma cell lines. Several had elevated expression of NIK due to genomic alterations or enhanced protein stability while others had inactivating mutations or deletion of TRAF3. Both abnormalities triggered the classical and alternative NF-kappaB pathways. A majority of primary myeloma patient samples and cell lines had elevated NF-kappaB target gene expression, often associated with genetic and epigenetic alteration of NIK, TRAF3, CYLD, BIRC2/BIRC3, CD40, NFKB1, and NFKB2. These genetic and functional data demonstrate that addiction to the NF-kappaB pathway is a frequent feature of myeloma and suggest that IKKbeta inhibitors hold promise for the treatment of this disease. Keywords: time series design
2007-10-29 | GSE8476 | GEO
Project description:Mechanisms of constitutive NF-kappaB signaling in multiple myeloma are unknown. An inhibitor of IkappaB kinase beta (IKKbeta), targeting the classical NF-kappaB pathway, was lethal to many myeloma cell lines. Several had elevated expression of NIK due to genomic alterations or enhanced protein stability while others had inactivating mutations or deletion of TRAF3. Both abnormalities triggered the classical and alternative NF-kappaB pathways. A majority of primary myeloma patient samples and cell lines had elevated NF-kappaB target gene expression, often associated with genetic and epigenetic alteration of NIK, TRAF3, CYLD, BIRC2/BIRC3, CD40, NFKB1, and NFKB2. These genetic and functional data demonstrate that addiction to the NF-kappaB pathway is a frequent feature of myeloma and suggest that IKKbeta inhibitors hold promise for the treatment of this disease. Keywords: time series design
2007-10-29 | GSE8477 | GEO
Project description:The paper describes a model of multiple myeloma.
Created by COPASI 4.26 (Build 213)
This model is described in the article:
A mathematical model of cell equilibrium and joint cell formation in multiple myeloma
M.A. Koenders, R. Saso
Journal of Theoretical Biology 390 (2016) 73–79
Abstract:
In Multiple Myeloma Bone Disease healthy bone remodelling is affected by tumour cells by means of paracrine cytokinetic signalling in such a way that osteoclast formation is enhanced and the growth of osteoblast cells inhibited. The participating cytokines are described in the literature. Osteoclast-induced myeloma cell growth is also reported. Based on existing mathematical models for healthy bone remo- delling a three-way equilibrium model is presented for osteoclasts, osteoblasts and myeloma cell populations to describe the progress of the illness in a scenario in which there is a secular increase in the cytokinetic interactive effectiveness of paracrine processes. The equilibrium state for the system is obtained. The paracrine interactive effectiveness is explored by parameter variation and the stable region in the parameter space is identified. Then recently-discovered joint myeloma–osteoclast cells are added to the model to describe the populations inside lytic lesions. It transpires that their presence expands the available parameter space for stable equilibrium, thus permitting a detrimental, larger population of osteoclasts and myeloma cells. A possible relapse mechanism for the illness is explored by letting joint cells dissociate. The mathematics then permits the evaluation of the evolution of the cell populations as a function of time during relapse.
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2024-09-02 | BIOMD0000000804 | BioModels
Project description:SUMOylation inhibition overcomes dexamethasone resistance in multiple myeloma
| PRJNA687056 | ENA
Project description:Patients with multiple myeloma refractory to standard treatments have short survival. High PDIA1 expression confers resistance to proteasome inhibitors and other stressors due to the gain in ER-function, while maintaining or increasing vulnerability to PDIA1 inhibition. In this study we report the identification and characterization of an orally bioavailable novel PDIA1 inhibitor CCF642-34 that is effective against multiple myeloma in pre-clinical models.
2021-02-20 | GSE167097 | GEO