Chronic Intermittent Hypoxia Exposure Promotes Multiple Myeloma Development in Black/6 Mice

Multiple myeloma (MM) is an incurable malignancy of bone marrow plasma B cells and is associated with obesity. The mechanisms by which obesity contributes to MM risk remains unclear, however, we speculate the linking factor to be sleep apnea which we simulated by chronic intermittent hypoxia (CIH). 5TGM1 cells are a murine MM cell line derived from the KaLwRij strain that fail to routinely engraft in Black6 mice. To test the hypothesis that chronic intermittent hypoxia (CIH) promotes the development of MM, we exposed MM-resistant C57BL/6 mice to 10h/day of CIH during the light cycle (AHI=10-12/h) for 7 days, or static 21% oxygen as a control. On day 7, mice were injected with 1x10⁶ GFP-labelled malignant mouse plasma cells (5TGM1) and the CIH was continued for an additional 28 days. 67% of the CIH mice developed MM, evidenced by paralysis, bone lesions in the spine, and plasmacytomas in the femur. It was also tested if the CIH effected the cells intrinsically. We hypothesized that CIH would promote the proliferation of 5TGM1 cells in culture. Two groups of 5TGM1 cells were plated in 18 gas permeable wells at a concentration of 500,000 cells/mL. One plate was placed in a plexiglass environmental control cabinet and the other plate was placed in a normoxia incubator. The incubator was maintained at 21% O₂ as a control. The environmental control cabinet, however, was maintained at an O₂ level that decreased to 10% for 90s, every five minutes, for 10 hours per day. The control plate showed normal signs of proliferation. On the other hand, the plate maintained in CIH conditions showed rapid cell death as early as Day 2 of the experiment. These results suggest that the CIH conditions do not cause growth and proliferation of the 5TGM1 cell line. Therefore, we speculate that CIH may exert its MM-promoting effects on the bone marrow stromal environment and not directly on the tumor. Future work in our laboratory will investigate the role of CIH in transforming the bone marrow microenvironment to allow for tumor cell engraftment.