Genetic Alterations in Members of the Proteasome 26S Subunit, AAA-ATPase (PSMC) Gene Family in the Light of Proteasome Inhibitor Resistance in Multiple Myeloma

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 com...

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Detalles Bibliográficos
Autores: Haertle, Larissa, Buenache, Natalia, Cuesta Hernández, Hipólito Nicolás, Simicek, Michal, Snaurova, Renata, Rapado, Inmaculada, Martinez, Nerea, López Muñoz, María de las Nieves, Sánchez Pina, José María, Munawar, Umair, Han, Seungbin, Ruiz Heredia, Yanira, Colmenares Gil, Rafael, Gallardo Delgado, Miguel, Sanchez Beato, Margarita, Piris, Miguel Angel, Samur, Mehmet Kemal, Munshi, Nikhil C., Ayala Díaz, Rosa María, Kortüm, Klaus Martin, Barrio, Santiago, Martínez López, Joaquín
Tipo de recurso: artículo
Fecha de publicación:2023
País:España
Institución:Universidad Complutense de Madrid (UCM)
Repositorio:Docta Complutense
Idioma:inglés
OAI Identifier:oai:docta.ucm.es:20.500.14352/72339
Acceso en línea:https://hdl.handle.net/20.500.14352/72339
Access Level:acceso abierto
Palabra clave:575
612.017
616.832-006
Multiple Myeloma
Drug resistance
Proteasome inhibitors
PSMC2
Immunoglobulin rearrangement
ATPase activity
Hematología
Oncología
3205.04 Hematología
3201.01 Oncología
Descripción
Sumario: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.

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