Genetic alterations in members of the proteasome 26S subunit, AAA-ATPase (PSMC) gene family in the light of proteasome inhibitor resistance in multiple myeloma

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00843989%3A_____%2F23%3AE0110204" target="_blank" >RIV/00843989:_____/23:E0110204 - isvavai.cz</a>

Alternative codes found

RIV/61988987:17110/23:A2402L2W

Result on the web

<a href="https://www.mdpi.com/2072-6694/15/2/532" target="_blank" >https://www.mdpi.com/2072-6694/15/2/532</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.3390/cancers15020532" target="_blank" >10.3390/cancers15020532</a>

Result language

angličtina

Original language name

Genetic alterations in members of the proteasome 26S subunit, AAA-ATPase (PSMC) gene family in the light of proteasome inhibitor resistance in multiple myeloma

Original language description

For the treatment of Multiple Myeloma, proteasome inhibitors are highly efficient and widely used, but resistance is a major obstacle to successful therapy. Several underlying mechanisms have been proposed but were only reported for a minority of resistant patients. The proteasome is a large and complex machinery. Here, we focus on the AAA ATPases of the 19S proteasome regulator (PSMC1-6) and their implication in PI resistance. As an example of cancer evolution and the acquisition of resistance, we conducted an in-depth analysis of an index patient by applying FISH, WES, and immunoglobulin-rearrangement sequencing in serial samples, starting from MGUS to newly diagnosed Multiple Myeloma to a PI-resistant relapse. The WES analysis uncovered an acquired PSMC2 Y429S mutation at the relapse after intensive bortezomib-containing therapy, which was functionally confirmed to mediate PI resistance. A meta-analysis comprising 1499 newly diagnosed and 447 progressed patients revealed a total of 36 SNVs over all six PSMC genes that were structurally accumulated in regulatory sites for activity such as the ADP/ATP binding pocket. Other alterations impact the interaction between different PSMC subunits or the intrinsic conformation of an individual subunit, consequently affecting the folding and function of the complex. Interestingly, several mutations were clustered in the central channel of the ATPase ring, where the unfolded substrates enter the 20S core. Our results indicate that PSMC SNVs play a role in PI resistance in MM.

Czech name

—

Czech description

—

Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

30205 - Hematology

Project

<a href="/en/project/EF17_049%2F0008440" target="_blank" >EF17_049/0008440: Cell Coolab Ostrava - Research and Development Center for Cell Therapy in Hematology and Oncology</a><br>

Continuities

V - Vyzkumna aktivita podporovana z jinych verejnych zdroju

Publication year

2023

Confidentiality

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

Name of the periodical

Cancers

ISSN

2072-6694

e-ISSN

2072-6694

Volume of the periodical

15

Issue of the periodical within the volume

article 532

Country of publishing house

CH - SWITZERLAND

Number of pages

12

Pages from-to

1-12

UT code for WoS article

000917027400001

EID of the result in the Scopus database

2-s2.0-85146774990