Sleep apnea is an underdiagnosed condition strongly associated with obesity, and linked to increased cancer mortality. Multiple myeloma is an incurable cancer of antibody-secreting bone marrow plasma cells associated with obesity, whose etiology is poorly understood. We found a previously unrecognized link between chronic intermittent hypoxia, a cardinal feature of sleep apnea, and myeloma in both patients and in a mouse model of myeloma. We found that 51% of myeloma clinic patients are at high risk of sleep apnea by questionnaire, and that sleep apnea risk was associated with a 10-fold increase in the serum free light ratio, a marker of disease burden. In our first 12 myeloma patients enrolled on a prospective nighttime oximetry trial, we found 11 patients (92%) to have evidence of nighttime hypoxia consistent with sleep apnea (20-fold increased risk compared to age-matched historical controls). In mice, we found that chronic intermittent hypoxia (CIH) stimulated myeloma cell bone marrow engraftment and lethal disease. CIH also caused gene expression changes in the bone marrow significantly associated with angiogenesis and B-cell development pathways. Here, we propose mechanistic studies in mice to test the hypothesis that CIH causes bone marrow microenvironment changes that support mutant plasma cell accumulation and disease progression:
Aim 1 : Test the hypothesis that intermittent hypoxia promotes the pathogenic expansion of mutated plasma cells in the bone marrow in additional models of myeloma;
Aim 2 : Map the anatomic changes to the bone marrow vasculature and macrophage populations, and effects on plasma cell distribution induced by intermittent hypoxia;
Aim 3 : Interrogate the mechanistic contributions of sympathetic-mediated signaling on bone marrow remodeling and lethal engraftment of myeloma cells. Together, these studies will elucidate the mechanisms by which CIH contributes to myeloma pathogenesis and will provide the foundation for clinical trials testing the role CIH in myeloma development and response to therapy.
The goal of this project is to determine how chronic intermittent hypoxia, a key feature of sleep apnea, impacts the the bone marrow to promote blood cancer. The results from the studies proposed here will provide information that may be used to develop treatments that prevent the progression from pre-malignancy to malignancy, thereby laying the groundwork for future studies in human patients.
