Bortezomib-resistant nuclear Factor-κB activity in multiple myeloma cells

Bortezomib (Velcade/PS341), a proteasome inhibitor used in the treatment of multiple myeloma (MM), can inhibit activation of nuclear factor-kappa B (NF-kappa B), a family of transcription factors often deregulated and constitutively activated in primary MM cells. NF-kappa B can be activated via several distinct mechanisms, including the proteasome inhibitor-resistant (PIR) pathway. It remains unknown what fraction of primary MM cells harbor constitutive NF-kappa B activity maintained by proteasome-dependent mechanisms. Here, we report an unexpected finding that constitutive NF-kappa B activity in 10 of 14 primary MM samples analyzed is refractory to inhibition by bortezomib. Moreover, when MM cells were cocultured with MM patient-derived bone marrow stromal cells (BMSC), microenvironment components critical for MM growth and survival, further increases in NF-kappa B activity were observed that were also refractory to bortezomib. Similarly, MM-BMSCs caused PIR NF-kappa B activation in the RPM18226 MM cell line, leading to increased NF-kappa B-dependent transcription and resistance to bortezomib-induced apoptosis. Our findings show that primary MM cells frequently harbor PIR NF-kappa B activity that is further enhanced by the presence of patient-derived BMSCs. They also suggest that this activity is likely relevant to the drug resistance development in some patients. Further elucidation of the mechanism of PIR NF-kappa B regulation could lead to the identification of novel diagnostic biomarkers and/or therapeutic targets for MM treatment.