Publication: Genetic Alterations in Members of the Proteasome 26S Subunit, AAA-ATPase (PSMC) Gene Family in the Light of Proteasome Inhibitor Resistance in Multiple Myeloma
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2023
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MDPI
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Abstract
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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This study was funded by Instituto de Salud Carlos III (ISCIII) and was co-funded by the European Union, through projects PI21/00314, PTQ2020-011372, and CP22/00082, and the CRIS Cancer Foundation. L.H. was funded by the DFG (Deutsche Forschungsgemeinschaft). through research fellowship HA 9529/1-1. M.K.S and N.C.M are funded by SPORE in Multiple Myeloma P50 CA100707 and Integrative Oncogenomics of Multiple Myeloma P01 CA155258. This work was furthermore supported by the project “Cell Coolab Ostrava—Research and Development Center for Cell Therapy in Hematology and Oncology” (No. C.Z.02.1.01/0.0/0.0/17_049/0008440) supported by ERDF.