[Identification of hypoxia-specific therapeutic targets in multiple myeloma]

The bone marrow microenvironment is low in oxygen, promoting a hypoxic response which causes myeloma cells to acquire stem cell properties and enhanced therapy resistance. We performed comprehensive gene and microRNA expression analyses of samples from myeloma patients and cell lines cultured under hypoxia. Through this, we identified the histone demethylase KDM3A, the glycolytic enzyme HK2, and microRNA-210 as factors playing important roles in the behavior of cells under hypoxic conditions. These genes were regulated by the hypoxia-inducible factor HIF. However, we also found that the expression of IRF4 and MYC, factors required for maintenance of differentiation and proliferation was suppressed by hypoxia. This suggests that the regulatory factors that induce drug resistance and the anti-apoptotic capacity of myeloma cells fluctuate with the partial pressure of oxygen in their environment. Based on this premise, a dual treatment strategy in which a dominant clone and a dormant clone adapted to the hypoxic microenvironment are treated simultaneously with orthogonal drugs is a potentially viable strategy to achieve a cure for multiple myeloma.