TY  - JOUR
A1  - Haertle, Larissa
A1  - Buenache, Natalia
A1  - Cuesta Hernández, Hipólito Nicolás
A1  - Simicek, Michal
A1  - Snaurova, Renata
A1  - Rapado, Inmaculada
A1  - Martinez, Nerea
A1  - López-Muñoz, Nieves
A1  - Sánchez-Pina, José María
A1  - Munawar, Umair
A1  - Han, Seungbin
A1  - Ruiz-Heredia, Yanira
A1  - Colmenares, Rafael
A1  - Gallardo, Miguel
A1  - Sanchez-Beato, Margarita
A1  - Piris, Miguel Angel
A1  - Samur, Mehmet Kemal
A1  - Munshi, Nikhil C.
A1  - Ayala, Rosa
A1  - Kortüm, Klaus Martin
A1  - Barrio, Santiago
A1  - Martínez-López, Joaquín
T1  - Genetic alterations in members of the proteasome 26S subunit, AAA-ATPase (PSMC) gene family in the light of proteasome inhibitor resistance in multiple myeloma
JF  - Cancers
N2  - 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.
KW  - Multiple Myeloma
KW  - drug resistance
KW  - proteasome inhibitors
KW  - immunoglobulin rearrangement
KW  - ATPase activity
KW  - PSMC2
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-305013
SN  - 2072-6694
VL  - 15
IS  - 2
ER  - 
TY  - JOUR
A1  - Ruiz-Heredia, Yanira
A1  - Sánchez-Vega, Beatriz
A1  - Onecha, Esther
A1  - Barrio, Santiago
A1  - Alonso, Rafael
A1  - Carlos Martínez-Avila, Jose
A1  - Cuenca, Isabel
A1  - Agirre, Xabier
A1  - Braggio, Esteban
A1  - Hernández, Miguel-T.
A1  - Martínez, Rafael
A1  - Rosiñol, Laura
A1  - Gutierrez, Norma
A1  - Martin-Ramos, Marisa
A1  - Ocio, Enrique M.
A1  - Echeveste, María-Asunción
A1  - Pérez de Oteyza, Jaime
A1  - Oriol, Albert
A1  - Bargay, Joan
A1  - Gironella, Mercedes
A1  - Ayala, Rosa
A1  - Bladé, Joan
A1  - Mateos, María-Victoria
A1  - Kortum, Klaus M.
A1  - Stewart, Keith
A1  - García-Sanz, Ramón
A1  - San Miguel, Jesús
A1  - José Lahuerta, Juan
A1  - Martinez-Lopez, Joaquín
T1  - Mutational screening of newly diagnosed multiple myeloma patients by deep targeted sequencing
JF  - Haematologica
N2  - no abstract available
KW  - Copy number changes
KW  - Survival
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227151
VL  - 103
IS  - 11
ER  -