Bortezomib Resistant Multiple Myeloma Cells Are Tumor Initiating Cells That Have a Stem Cell-Like Genetic Signature.

Abstract 2805

Poster Board II-781

Bortezomib, a proteasome inhibitor, effectively suppresses survival and growth of multiple myeloma (MM) cells. It can inhibit activation of nuclear factor-kB (NF-kB) and has been used in the treatment of MM. However, recent studies reported that patients with relapsed or refractory MM acquired resistance against bortezomib during disease progression. Therefore, we need to elucidate the molecular mechanism by which resistance emerges and this is crucial for improving treatment outcome by potentiating therapeutic efficacy of bortezomib in MM. Here, we established bortezomib resistant MM cells (U266/vel R) using soft-agar assay and identified the major molecular events that are related with acquired resistance against bortezomib. MTT assay showed that U266/Vel R cells have a growth advantage over bortezomib and the endogenous levels of pERK and pSTAT-3, -5 in U266/vel R were higher than those in parental cells. The expression of a set of genes associated with cancer stem cells was up-regulated in U266/vel R. FACS analysis showed that side population was gradually increased when U266 cells were serially exposed to bortezomib. In addition, increasing number of CD138 negative U266 cells were found in U266/ vel R cell population. It suggested that surviving cells in the presence of bortezomib could be MM cancer stem cells. Our data strongly suggest that biologic characteristics of bortezomib resistant MM cells are mediated by these potential cancer stem cells.