Bortezomib-resistant nuclear factor-kappaB activity in multiple myeloma cells

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• Bortezomib is a proteasome inhibitor used for multiple myeloma (MM).
• Nuclear factor-kappaB (NF-kappaB) is often deregulated in MM cells.
• NF-kappaB can be activated through proteasome inhibitor-resistant (PIR) pathways.

Purpose of the Study:

• To determine the prevalence of constitutive NF-kappaB activity in primary MM cells.
• To investigate the role of the bone marrow microenvironment in NF-kappaB activation and bortezomib resistance.
• To explore potential therapeutic targets for overcoming drug resistance in MM.

Main Methods:

• Analysis of constitutive NF-kappaB activity in 14 primary MM samples.
• Co-culture experiments with MM cells and patient-derived bone marrow stromal cells (BMSCs).
• Assessment of NF-kappaB activity, NF-kappaB-dependent transcription, and apoptosis in response to bortezomib.

Main Results:

• Constitutive NF-kappaB activity was refractory to bortezomib in 10 of 14 primary MM samples.
• Co-culture with BMSCs further increased NF-kappaB activity, which was also bortezomib-refractory.
• MM-BMSCs induced PIR NF-kappaB activation and bortezomib resistance in the RPMI8226 MM cell line.

Conclusions:

• Primary MM cells frequently exhibit PIR NF-kappaB activity.
• Patient-derived BMSCs enhance PIR NF-kappaB activity and contribute to bortezomib resistance.
• PIR NF-kappaB regulation may represent a novel therapeutic target and diagnostic biomarker for MM treatment.