Bone marrow stromal cells from multiple myeloma patients uniquely induce bortezomib resistant NF-κB activity in myeloma cells

Abstract

BackgroundComponents of the microenvironment such as bone marrow stromal cells (BMSCs) are well known to support multiple myeloma (MM) disease progression and resistance to chemotherapy including the proteasome inhibitor bortezomib. However, functional distinctions between BMSCs in MM patients and those in disease-free marrow are not completely understood. We and other investigators have recently reported that NF-κB activity in primary MM cells is largely resistant to the proteasome inhibitor bortezomib, and that further enhancement of NF-κB by BMSCs is similarly resistant to bortezomib and may mediate resistance to this therapy. The mediating factor(s) of this bortezomib-resistant NF-κB activity is induced by BMSCs is not currently understood.ResultsHere we report that BMSCs specifically derived from MM patients are capable of further activating bortezomib-resistant NF-κB activity in MM cells. This induced activity is mediated by soluble proteinaceous factors secreted by MM BMSCs. Among the multiple factors evaluated, interleukin-8 was secreted by BMSCs from MM patients at significantly higher levels compared to those from non-MM sources, and we found that IL-8 contributes to BMSC-induced NF-κB activity.ConclusionsBMSCs from MM patients uniquely enhance constitutive NF-κB activity in MM cells via a proteinaceous secreted factor in part in conjunction with IL-8. Since NF-κB is known to potentiate MM cell survival and confer resistance to drugs including bortezomib, further identification of the NF-κB activating factors produced specifically by MM-derived BMSCs may provide a novel biomarker and/or drug target for the treatment of this commonly fatal disease.

A novel BCMA/CD3 bispecific T-cell engager for the treatment of multiple myeloma induces selective lysis in vitro and in vivo

“…We observed (data not shown) that the T cells reach their maximal cell size after 72 h of incubation, assuming that this time is needed for the T cells to prepare for progressing through the cell cycle. This finding is in line with published data showing T-cell proliferation after 5 days, whereas cell lysis was already seen after 24 h. 29 BMSCs are known to protect MM cells from apoptosis and can be involved in drug resistance, 23 therefore we tested BI 836909 in in vitro assays where we co-cultured BMSCs with two different MM 3 . Then mice were injected with activated and ex vivo expanded human T cells into the peritoneal cavity.…”

“…[15][16][17][18][19][20][21] BCMA is also expressed on plasmacytoid dendritic cells, which promote MM cell growth, survival and drug resistance. [21][22][23] Expression levels on plasmacytoid dendritic cells are also elevated in MM patients versus normal donors. 21 Apart from expression on peripheral and bone marrow resident plasma cells and plasmacytoid dendritic cells, BCMA is not expressed on naive and most memory B cells, CD34+ hematopoietic cells, or any other normal tissue cells.…”

Investigating osteogenic differentiation in multiple myeloma using a novel 3D bone marrow niche model

“…8 MM patient-derived MSCs (MM-MSCs) exhibit decreased proliferation and osteogenesis and an inability to repair osteolytic damage, and they display great patient-to-patient heterogeneity in their ability to undergo differentiation and induce changes in MM cells. [8][9][10] The tumor BM microenvironment also supports tumor growth, 11 induces chemoresistance, and selects for tumor-initiating clones. 12 Therefore, a realistic model of the abnormal BM seen in MM patients would greatly benefit translational research scientists.…”

Multiple myeloma–derived MMP-13 mediates osteoclast fusogenesis and osteolytic disease

“…In vivo, BM stromal cells (BMSCs) are known to support MM cell growth and survival via both contact-dependent and -independent mechanisms (20,21). Hence, we next determined whether BMSCs contribute to MMP-13 upregulation in MM cells.…”