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Single-nucleotide variants and epimutations induce proteasome inhibitor resistance in multiple myeloma

Identifikátory výsledku

  • Kód výsledku v IS VaVaI

    <a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00843989%3A_____%2F23%3AE0110257" target="_blank" >RIV/00843989:_____/23:E0110257 - isvavai.cz</a>

  • Nalezeny alternativní kódy

    RIV/61988987:17110/23:A2402N74

  • Výsledek na webu

    <a href="https://aacrjournals.org/clincancerres/article-abstract/29/1/279/711985/Single-Nucleotide-Variants-and-Epimutations-Induce?redirectedFrom=fulltext" target="_blank" >https://aacrjournals.org/clincancerres/article-abstract/29/1/279/711985/Single-Nucleotide-Variants-and-Epimutations-Induce?redirectedFrom=fulltext</a>

  • DOI - Digital Object Identifier

    <a href="http://dx.doi.org/10.1158/1078-0432.CCR-22-1161" target="_blank" >10.1158/1078-0432.CCR-22-1161</a>

Alternativní jazyky

  • Jazyk výsledku

    angličtina

  • Název v původním jazyce

    Single-nucleotide variants and epimutations induce proteasome inhibitor resistance in multiple myeloma

  • Popis výsledku v původním jazyce

    Purpose: Proteasome inhibitors (PI) are the backbone of various treatment regimens in multiple myeloma. We recently described the first in-patient point mutations affecting the 20S subunit PSMB5 underlying PI resistance. Notably, in vivo, the incidence of mutations in PSMB5 and other proteasome encoding genes is too low to explain the development of resistance in most of the affected patients. Thus, additional genetic and epigenetic alterations need to be explored. Experimental design: We performed DNA methylation profiling by Deep Bisulfite Sequencing in PSMB5, PSMC2, PSMC5, PSMC6, PSMD1, and PSMD5, a subset of proteasome subunits that have hitherto been associated with PI resistance, recruited from our own previous research, the literature, or a meta-analysis on the frequency of somatic mutations. Methylation was followed up on gene expression level and by dual-luciferase reporter assay. The KMS11 cell line served as a model to functionally test the impact of demethylating agents. Results: We identified PSMD5 promoter hypermethylation and subsequent epigenetic gene silencing in 24% of PI refractory patients. Hypermethylation correlated with decreased expression and the regulatory impact of this region was functionally confirmed. In contrast, patients with newly diagnosed multiple myeloma, along with peripheral blood mononuclear cells and CD138+ plasma cells from healthy donors, generally show unmethylated profiles. Conclusions: Under the selective pressure of PI treatment, multiple myeloma cells acquire methylation of the PSMD5 promoter silencing the PSMD5 gene expression. PSMD5 acts as a key orchestrator of proteasome assembly and its downregulation was described to increase the cell's proteolytic capacity. PSMD5 hypermethylation, therefore, represents a novel mechanism of PI tolerance in multiple myeloma.

  • Název v anglickém jazyce

    Single-nucleotide variants and epimutations induce proteasome inhibitor resistance in multiple myeloma

  • Popis výsledku anglicky

    Purpose: Proteasome inhibitors (PI) are the backbone of various treatment regimens in multiple myeloma. We recently described the first in-patient point mutations affecting the 20S subunit PSMB5 underlying PI resistance. Notably, in vivo, the incidence of mutations in PSMB5 and other proteasome encoding genes is too low to explain the development of resistance in most of the affected patients. Thus, additional genetic and epigenetic alterations need to be explored. Experimental design: We performed DNA methylation profiling by Deep Bisulfite Sequencing in PSMB5, PSMC2, PSMC5, PSMC6, PSMD1, and PSMD5, a subset of proteasome subunits that have hitherto been associated with PI resistance, recruited from our own previous research, the literature, or a meta-analysis on the frequency of somatic mutations. Methylation was followed up on gene expression level and by dual-luciferase reporter assay. The KMS11 cell line served as a model to functionally test the impact of demethylating agents. Results: We identified PSMD5 promoter hypermethylation and subsequent epigenetic gene silencing in 24% of PI refractory patients. Hypermethylation correlated with decreased expression and the regulatory impact of this region was functionally confirmed. In contrast, patients with newly diagnosed multiple myeloma, along with peripheral blood mononuclear cells and CD138+ plasma cells from healthy donors, generally show unmethylated profiles. Conclusions: Under the selective pressure of PI treatment, multiple myeloma cells acquire methylation of the PSMD5 promoter silencing the PSMD5 gene expression. PSMD5 acts as a key orchestrator of proteasome assembly and its downregulation was described to increase the cell's proteolytic capacity. PSMD5 hypermethylation, therefore, represents a novel mechanism of PI tolerance in multiple myeloma.

Klasifikace

  • Druh

    J<sub>imp</sub> - Článek v periodiku v databázi Web of Science

  • CEP obor

  • OECD FORD obor

    30205 - Hematology

Návaznosti výsledku

  • Projekt

    <a href="/cs/project/EF18_069%2F0010060" target="_blank" >EF18_069/0010060: Nové směry biomedicínského výzkumu na Ostravsku</a><br>

  • Návaznosti

    V - Vyzkumna aktivita podporovana z jinych verejnych zdroju

Ostatní

  • Rok uplatnění

    2023

  • Kód důvěrnosti údajů

    S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Údaje specifické pro druh výsledku

  • Název periodika

    Clinical cancer research

  • ISSN

    1078-0432

  • e-ISSN

    1557-3265

  • Svazek periodika

    29

  • Číslo periodika v rámci svazku

    1

  • Stát vydavatele periodika

    US - Spojené státy americké

  • Počet stran výsledku

    10

  • Strana od-do

    279-288

  • Kód UT WoS článku

    000908379600001

  • EID výsledku v databázi Scopus

    2-s2.0-85145492234