Single-Nucleotide Variants and Epimutations Induce Proteasome Inhibitor Resistance in Multiple Myeloma.

Area of Science:

• Oncology
• Molecular Biology
• Epigenetics

Background:

• Proteasome inhibitors (PI) are crucial for multiple myeloma treatment.
• Existing PI resistance mechanisms, like PSMB5 mutations, are insufficient to explain most cases.
• Further investigation into genetic and epigenetic alterations is needed to understand PI resistance.

Approach:

• DNA methylation profiling using Deep Bisulfite Sequencing was performed on key proteasome subunits (PSMB5, PSMC2, PSMC5, PSMC6, PSMD1, PSMD5).
• Methylation analysis was correlated with gene expression levels and functional assays (dual-luciferase reporter assay).
• The KMS11 cell line was used to test the effects of demethylating agents.

Key Points:

• PSMD5 promoter hypermethylation and subsequent gene silencing were identified in 24% of PI-refractory multiple myeloma patients.
• This epigenetic silencing correlated with decreased PSMD5 expression.
• Unmethylated PSMD5 promoter profiles were observed in newly diagnosed patients and healthy donors.

Conclusions:

• Proteasome inhibitor treatment pressure induces PSMD5 promoter methylation and gene silencing in multiple myeloma cells.
• Downregulation of PSMD5, a key proteasome assembly factor, enhances cellular proteolytic capacity, contributing to PI tolerance.
• PSMD5 hypermethylation represents a novel epigenetic mechanism driving proteasome inhibitor tolerance in multiple myeloma.