Objective:

To identify strategies to improve bortezomib sensitivity in multiple myeloma (MM) by investigating the role of miR-1248.

Approach:

• RNA-seq Screening: Screened bortezomib-responsive miRNAs in RPMI8226 cells.
• qRT-PCR and Western Blot: Measured miR-1248 and MEF2C expression in MM cells and plasma from patients.
• Luciferase Assays: Tested miR-1248 binding to the MEF2C 3′-UTR.
• Inhibition and Overexpression Experiments: Inhibited miR-1248 and overexpressed MEF2C to assess effects on autophagy and apoptosis.
• Xenograft Model: Used a xenograft model to evaluate tumor response to miR-1248 inhibition plus bortezomib.

Key Findings:

• Bortezomib increased miR-1248 expression by 2-fold and reduced MEF2C mRNA by 62% and protein by 55%.
• Plasma miR-1248 levels rose after VCD therapy in patients.
• miR-1248 directly targets the MEF2C 3′-UTR.
• Inhibition of miR-1248 reduced autophagy markers and restored MEF2C and p38 expression.
• MEF2C overexpression decreased bortezomib-induced apoptosis.
• In xenografts, miR-1248 knockdown reduced tumor inhibition significantly.

Interpretation:

miR-1248 enhances bortezomib sensitivity in MM by targeting MEF2C, leading to reduced p38 expression and autophagic activity.

Limitations:

• Study conducted on a limited number of patient samples (30).
• In vivo results based on a single xenograft model.

Conclusion:

miR-1248 may serve as a potential therapeutic target to improve bortezomib response in multiple myeloma.