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