Abstract
Abstract 3943
Myeloma plasma cell high labeling index and molecular signature of proliferation are strong adverse prognostic factors often characterize patients with high risk disease. The overall aim of the study was to identify cell proliferation associated genes implicating highly proliferating myeloma cells in the supportive bone marrow environment. To shed light on molecular factors associated with rapid growth of myeloma cells, primary myeloma cells from 10 patients, molecularly classified as high risk were engrafted in SCID-rab mice. Growth rate of myeloma varied between patients' cells but in all cases myeloma propagated within and surrounding the supportive implanted bone but not in any murine organs. We performed global gene expression profiling (GEP) on myeloma plasma cells recovered from mice and compared their GEP with the baseline, pre-injected myeloma cells. Based on stringent criteria (e.g. p<0.05, >2 folds) approximately 127 probe sets were commonly overexpressed and 36 probe sets underexpressed in myeloma cells from SCID-rab mice than baseline myeloma cells. Genes whose expression altered were mainly associated with proliferation, survival, metabolism, transcription and immunity. Among genes involved in cell proliferation we indentified stearoyl CoA desaturase 1 (SCD1), which was upregulated in 7 of 10 cases by overall 2.3±0.6 folds (p<0.01). In coculture of primary myeloma cells with the supportive osteoclasts (n=8), SCD1 was upregulated in 6 of 8 cocultures by 5.6±2.4 folds (p<0.02). SCD1 upregulation in vivo and in cocultures was consistently observed in 3 different GEP probe sets. SCD1 is a rate-limiting enzyme responsible for synthesis of monounsaturated fatty acids and is activated in highly proliferating tumor cells to sustain the increasing demand of new membrane phospholipids and energy storage, and reducing intracellular content of cytotoxic saturated fatty acids. Various SCD1 inhibitors are currently being evaluated for metabolic diseases. In vitro, small molecule SCD1 inhibitor (BioVision) dose dependently (0.1–10 μM, 96 hrs) inhibited growth of rapidly growing myeloma cell lines (n=5) but had moderate inhibitory effect on their survival. Compared to control vehicle-treated cultures, numbers of viable myeloma cells were reduced by 76±5% (p<0.008) and 51±3% (p<0.0001) following treatment with 0.1 μM and 5 μM of SCD1 inhibitor, respectively. Cell viability was reduced from 91±0.5% in control groups to 82±3% (p<0.05) and 73±5% (p<0.03) in cultures treated with 0.1 μM and 5 μM of SCD1 inhibitor, respectively. In vivo, luciferase-expressing H929 myeloma cells were engrafted in SCID-rab mice. Myeloma growth was monitored by live-animal bioluminescence imaging. Upon establishment of myeloma hosts were treated with SCD1 inhibitor using Alzet osmotic pump directly connected to the open side of the implanted bone and constantly released drug (1.25 μg/hour) or vehicle over a period of 2 weeks. At experiment's end myeloma burden was increased from pretreatment levels by 49±3 folds and 30±3 folds in control vehicle- and SCD1 inhibitor-treated hosts, respectively (p<0.01). We conclude that SCD1 is highly activated in proliferating myeloma cells and is essential for their rapid growth.
Disclosures:
No relevant conflicts of interest to declare.
Stearoyl-CoA desaturase-1 impairs the reparative properties of macrophages and microglia in the brain