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The proteasome inhibitor bortezomib has a striking clinical benefit in patients with multiple myeloma. It is unknown whether the bone marrow microenvironment directly contributes to the dramatic response of myeloma cells to proteasome inhibition in vivo. We have used the well-characterized 5TGM1 murine model of myeloma to investigate myeloma growth within bone and response to the proteasome inhibitor bortezomib in vivo. Myeloma cells freshly isolated from the bone marrow of myeloma-bearing mice were found to have an increase in proteasome activity and an enhanced response to in vitro proteasome inhibition, as compared with pre-inoculation myeloma cells. Treatment of myeloma-bearing mice with bortezomib resulted in a greater reduction in tumor burden when the myeloma cells were located within the bone marrow when compared with extra-osseous sites. Our results demonstrate that myeloma cells exhibit an increase in proteasome activity and an enhanced response to bortezomib treatment when located within the bone marrow microenvironment in vivo.

Original publication

DOI

10.1002/ajh.21374

Type

Journal article

Journal

American journal of hematology

Publication Date

05/2009

Volume

84

Pages

268 - 272

Addresses

Vanderbilt Center for Bone Biology, Department of Cancer Biology, Vanderbilt University, 1235 Medical Research Building IV, Nashville, TN 37232-0575, USA. claire.edwards@vanderbilt.edu

Keywords

Bone Marrow Cells, Cell Line, Tumor, Bone Marrow, Animals, Mice, Multiple Myeloma, Boronic Acids, Pyrazines, Proteasome Endopeptidase Complex, Immunoglobulin G, Protease Inhibitors, Tumor Burden, Neoplasm Transplantation, Cell Communication, Enzyme Activation, Proteasome Inhibitors, Bortezomib