Bone marrow stromal cells from multiple myeloma patients uniquely induce bortezomib resistant NF-kappaB activity in myeloma cells.
BACKGROUND
Components 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-kappaB activity in primary MM cells is largely resistant to the proteasome inhibitor bortezomib, and that further enhancement of NF-kappaB by BMSCs is similarly resistant to bortezomib and may mediate resistance to this therapy. The mediating factor(s) of this bortezomib-resistant NF-kappaB activity is induced by BMSCs is not currently understood.


RESULTS
Here we report that BMSCs specifically derived from MM patients are capable of further activating bortezomib-resistant NF-kappaB 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-kappaB activity.


CONCLUSIONS
BMSCs from MM patients uniquely enhance constitutive NF-kappaB activity in MM cells via a proteinaceous secreted factor in part in conjunction with IL-8. Since NF-kappaB is known to potentiate MM cell survival and confer resistance to drugs including bortezomib, further identification of the NF-kappaB 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.
Markovina
Stephanie
S
Program in Cellular and Molecular Biology and Medical Science Training Program, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53705, USA. smiyamot@facstaff.wisc.edu
Callander
Natalie S
NS
O'Connor
Shelby L
SL
Xu
Guangwu
G
Shi
Yufang
Y
Leith
Catherine P
CP
Kim
KyungMann
K
Trivedi
Parul
P
Kim
Jaehyup
J
Hematti
Peiman
P
Miyamoto
Shigeki
S
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001854:Bone Marrow Cells / Q000473:pathology*; D001897:Boronic Acids / Q000627:therapeutic use*; D000069286:Bortezomib; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism*; D011719:Pyrazines / Q000627:therapeutic use*; D017154:Stromal Cells / Q000473:pathology*
D000970:Antineoplastic Agents; D001897:Boronic Acids; D016209:Interleukin-8; D016328:NF-kappa B; D011719:Pyrazines; D000069286:Bortezomib