Bone marrow milieu reprogramming triggered by chronic intermittent hypoxia

Sleep apnea is a common condition that often goes undiagnosed, but it is associated with cardiovascular disease and an increased cancer mortality risk. Patients suffering from sleep apnea go through frequent episodes during the night where their breathing stops, causing a reduction in the oxygen levels in their blood. This condition is referred to as “chronic intermittent hypoxia.” In our lab, we have found that chronic intermittent hypoxia promoted the onset of multiple myeloma, a cancer of bone marrow plasma cells, in mice. We focused on understanding how chronic intermittent hypoxia affects the bone marrow microenvironment. We exposed mice to chronic intermittent hypoxia and assessed the impact on the bone marrow immune cells. Chamber systems are commonly used to perform intermittent hypoxia exposures. However, before revealing physiological alterations induced by intermittent hypoxia, understanding the factors contributing to variability in intermittent hypoxia experiments is crucial to enhancing reproducibility.

In this thesis, our data highlights the significant factors of variability, emphasizing the necessity to report and validate the target oxygen concentration, cycling frequency, and arterial oxygen concentration. Using the optimized intermittent hypoxia protocol, we found chronic intermittent induced macrophage and B cell gene signatures in the bone marrow, which is shared by KaLwRij myeloma-prone mice. These differentially expressed macrophage genes are clustered in several subsets of B cell lineage and a single cell population consistent with erythroid island macrophages and distinct from “traditional macrophages.” The research contributes to our comprehension of the physiological implications of intermittent hypoxia.