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Exosomes mediate intercellular transference of non-autonomous tolerance to proteasome inhibitors in mixed-lineage leukemia.

ABSTRACT: The interplay between cancer cells and microenvironment can influence treatment response and plays a key role in the emergence of drug resistance. Rapidly acquired resistance prevents proteasome inhibitors (PIs) therapies from achieving stable and complete responses. Investigating the underlying mechanisms and developing effective strategies against PI resistance are highly desired in the clinic. Here we uncovered that PI resistance was reversible in mixed-lineage leukemia (MLL), which consistent with the finding that patients could regain sensitivity to PIs after a drug holiday. Exosomes released from PI-treated cells could transmit PI resistance to sensitive cells via facilitating cell cycle arrest and stemness pathway in MLL cells. Furthermore, TieDIE algorithm integration analysis of transcriptome and proteome datasets identified candidate exosomal proteins, providing potential therapeutic targets for treating refractory MLL.

OTHER RELATED OMICS DATASETS IN: PXD014711

ORGANISM(S): Homo sapiens

PROVIDER: GSE134879 | GEO | 2020/04/22

REPOSITORIES: GEO

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Drug-tolerant cell-derived exosomes regulate proteasome inhibitor resistance pathways in MLL leukemias

Project description:The interplay between cancer cells and microenvironment can influence treatment response and plays a key role in the emergence of drug resistance. Rapidly acquired resistance prevents proteasome inhibitors (PIs) therapies from achieving stable and complete responses. Investigating the underlying mechanisms and developing effective strategies against PI resistance are highly desired in the clinic. Here we uncovered that PI resistance was reversible in MLL leukemia, which consistent with the finding that patients could regain sensitivity to PIs after a drug holiday. Exosomes derived from drug-tolerant cells could transmit PI resistance to sensitive cells via facilitating cell cycle arrest and stemness pathway in MLL leukemia cells. Furthermore, TieDIE algorithm integration analysis of transcriptome and proteome datasets identified candidate exosomal proteins, providing potential therapeutic targets for treating refractory MLL leukemia. Therefore, exosomal regulatory proteins may serve as a predictor and a potential therapeutic target for PI resistance, and inhibiting the secretion of exosomes is a promising strategy for restoring PI resistance in vivo, which provides a paradigm and may also be applied for the treatment of other cancers resulting from chemotherapy relapse.

2020-05-27 | PXD014711 | Pride

Restoring chromatin accessibility for MLL reactivates latent tumor suppression-mediated vulnerability to proteasome inhibitors.

Project description:MLL undergoes multiple distinct chromosomal translocations to yield aggressive leukemia with dismal outcomes. Besides their well-established role in leukemogenesis, MLL fusions also possess latent tumor suppressive activity which can be exploited as effective cancer treatment strategies using pharmacological means such as proteasome inhibitors (PIs). Here, we show that wild-type MLL is indispensable for the latent tumor suppressive activity of MLL fusions. MLL dysfunction, shown as loss of the chromatin accessibility and subsequent degradation of MLL, compromises the latent tumor suppressive activity of MLL fusions and is instrumental for the acquired PI resistance. Mechanistically, MLL dysfunction is caused by chronic PI treatment-induced epigenetic reprogramming and can be specifically restored by histone deacetylase (HDAC) inhibitors.

2020-09-21 | GSE138177 | GEO

Clinical drug resistance linked to reversible phenotypic transition and epigenetic alteration in multiple myeloma

Project description:The development of proteasome inhibitors (PIs) for the treatment of multiple myeloma (MM) has dramatically increased treatment responses and improved survival. The first-in-class PI, bortezomib, was used in a twice-weekly intravenous as a sustained single or combinational regimen for relapsed and subsequently for newly diagnosed MM. The relatively rapid acquisition of drug resistance to PI treatment remains a crucial obstacle. Gradual familiarity with toxicity and optimizing dose schedules have formed the current use of PIs as key components in promoting response and eliminating resistance. Combination therapies and schedule adaptation to once-weekly use of PIs have meanwhile been shown to be both more tolerable and highly efficacious. Interestingly, patients may remain sensitive to PIs after relapse of initial therapy, implying that PI resistance is reversible and suggest a previously unrecognized drug resistance mechanism via epigenetic changes that may be intrinsic to PI treatment.

2021-02-24 | GSE136725 | GEO

Proteasome inhibitor-induced modulation reveals the spliceosome as a specific therapeutic vulnerability in multiple myeloma

Project description:Resistance to proteasome inhibitors (PIs) is a ubiquitous clinical concern in multiple myeloma (MM). We proposed that signaling-level responses after PI would reveal new means to enhance efficacy. Unbiased phosphoproteomics after the PI carfilzomib surprisingly demonstrated the most prominent phosphorylation changes on spliceosome components. Spliceosome modulation was invisible to RNA or protein abundance alone. Transcriptome analysis demonstrated broad-scale intron retention suggestive of PI-specific splicing interference. Direct spliceosome inhibition synergized with carfilzomib and showed potent anti-myeloma activity. Functional genomics and exome sequencing further supported the spliceosome as a specific vulnerabilityin myeloma. Our results propose splicing interference as an unrecognized modality of PI mechanism, reveal additional modes of spliceosome modulation, and suggest spliceosome targeting as a promising therapeutic strategy in myeloma.

2020-02-18 | GSE124510 | GEO

Proteasome inhibitor-induced modulation reveals the spliceosome as a specific therapeutic vulnerability in multiple myeloma

Project description:Resistance to proteasome inhibitors (PIs) is a ubiquitous clinical concern in multiple myeloma. We proposed that signaling-level responses after PI would reveal new means to enhance efficacy. Unbiased phosphoproteomics after the PI carfilzomib surprisingly demonstrated the most prominent phosphorylation changes on spliceosome components. Spliceosome modulation was invisible to RNA or protein abundance alone. Transcriptome analysis demonstrated broad-scale intron retention suggestive of PI-specific splicing interference. Direct spliceosome inhibition synergized with carfilzomib and showed potent anti-myeloma activity. Functional genomics and exome sequencing further supported the spliceosome as a specific vulnerability in myeloma. Our results propose splicing interference as an unrecognized modality of PI mechanism, reveal additional modes of spliceosome modulation, and suggest spliceosome targeting as a promising therapeutic strategy in myeloma.

2020-02-21 | PXD012172 | Pride

HRP2-MINA complex reprograms t(4;14) multiple myeloma epigenome to dictate chemosensitivity to proteasome inhibitors [RNA-Seq]

Project description:Depletion of HRP2 induced remarkable resistance to PIs induced apoptosis of MM cells in vitro and in vivo, and suppressed expression of HRP2 was observed in bortezomib-resistant (BR) MM cells. Notably, HRP2 altered chemosensitivity more obviously in MM cells with t(4;14) translocation, and much remarkable resistant to PIs than other reagents. Moreover, HRP2 abolition of HRP2 augmented H3K27me3 modification, consequentially intensifying transcriptome alteration prone to cell survival and restriction of endoplasmic reticulum (ER) stress. Mechanistically, HRP2 recognized H3K36me2 and recruited the histone demethylases MYC-induced nuclear antigen (MINA) to degrade H3K27me3, released suppression on genes responsible for drug resistance, such as ATF3 and NR4A1. Thus, an EZH2 inhibitor, tazemetostat, synergistically sensitized anti-MM effect of bortezomib both in vitro and in vivo. Collectively, our study provides novel knowledge to understand the origination of chemoresistance in MM patients with t(4;14), and rationale for managing MM patients according to different genomic backgrounds.

2021-02-11 | GSE166524 | GEO

Secondary proteasome inhibitor carfilzomib resistant myeloma cell lines

Project description:Modulation of the activity of the ubiquitin-proteasome pathway with the proteasome inhibitor (PI) is an established component of therapy for plasma cell disorders. However, resistance emerges and the mechanism is incompletely understood. We generated carfilzomib-resistant (CR) myeloma cell lines by exposing drug-naive ANBL-6, KAS-6/1, U266, and OPM-2 cells to increasing concentrations of carfilzomib and then performed gene expression profiling (GEP) to identify prominent changes compared to their vehicle-treated counterparts, followed by exploration of the mechanism(s) of proteasome inhibitor resistance.

2016-10-09 | GSE62237 | GEO

CRIP1 involves the pathogenesis of multiple myeloma via dual-regulation of proteasome and autophagy

Project description:Multiple myeloma (MM) is an incurable hematological malignancy of plasma cells. The maintenance of protein homeostasis is critical for the survival of MM cells. The excess paraprotein in MM cells undergoes clearance through proteasomes or lysosomes, two inter-connected yet independent pathways. While proteasome inhibitors (PIs) serve as fundamental agents significantly improving patient outcomes, heightened autophagy activity diminishes sensitivity to PI treatment.Elevated CRIP1 levels serve as a biomarker for relapsed/refractory MM and correlate with shorter overall patient survival. To further comprehend the role of CRIP1 in multiple myeloma pathogenesis, we conducted transcriptome sequencing.

2023-11-27 | GSE248339 | GEO

Allosteric HSP70 inhibitors perturb mitochondrial proteostasis and overcome proteasome inhibitor resistance in multiple myeloma

Project description:Proteasome inhibitor (PI) resistance remains a central challenge in multiple myeloma. To identify pathways mediating resistance, we first map proteasome-associated genetic co-dependencies. We identify cytosolic heat shock protein 70 (HSP70) chaperones as a potential target, consistent with proposed mechanisms of myeloma tumor cells overcoming PI-induced stress. These results led us to explore allosteric HSP70 inhibitors as myeloma therapeutics. We show these compounds exhibit increased efficacy against both acquired and intrinsic PI-resistant myeloma models, unlike HSP90 inhibition. Surprisingly, shotgun and pulsed-SILAC proteomics reveal that JG’s overcome PI resistance not via the expected mechanism of inhibiting cytosolic HSP70s, but instead through mitochondrial-localized HSP70, HSPA9, destabilizing the 55S mitoribosome. Analysis of myeloma patient data further supports strong effects of global proteostasis capacity, and particularly HSPA9 expression, on PI response. Our results characterize dynamics of myeloma proteostasis networks under therapeutic pressure while further motivating investigation of HSPA9 as a specific target in PI-resistant disease.

2020-04-15 | GSE148659 | GEO

Allosteric HSP70 inhibitors in Proteasome Inhibitor Resistant Multiple Myeloma

Project description:Proteasome inhibitor (PI) resistance remains a central challenge in multiple myeloma. To identify pathways mediating resistance, we first mapped proteasome-associated genetic co-dependencies. We identified cytosolic heat shock protein 70 (HSP70) chaperones as potential targets, consistent with proposed mechanisms of myeloma tumor cells overcoming PI-induced stress. These results led us to explore allosteric HSP70 inhibitors (JG compounds) as myeloma therapeutics. We showed these compounds exhibit increased efficacy against acquired and intrinsic PI-resistant myeloma models, unlike HSP90 inhibition. Surprisingly, shotgun and pulsed-SILAC mass spectrometry found that JGs have the most pronounced effect on the proteome not through inhibiting cytosolic HSP70s but instead through mitochondrial-localized HSP70, HSPA9/mortalin, destabilizing the 55S mitoribosome. Analysis of myeloma patient data further supports strong effects of global proteostasis capacity, and particularly HSPA9 expression, on PI response. Our results characterize myeloma proteostasis networks under therapeutic pressure while motivating further investigation of HSPA9 as a specific vulnerability in PI-resistant disease.

2022-05-27 | PXD032030 | Pride

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