RNA Bulk Sequencing Analysis and Differential Gene Expression of Multiple Myeloma Susceptibility Strains: KaLwRij and CIH

Multiple myeloma is a terminal cancer of bone marrow plasma cells whose pathophysiological mechanisms remain poorly understood. Similar genetic mutations are shared between myeloma and its requisite pre‐malignant phase MGUS, suggesting that other factors are required for disease progression. There are two mouse strains that are susceptible to the lethal engraftment of malignant plasma cells. KaLwRij is a tumor‐receptive, spontaneous mutant of the control mouse C57BL/6J and has a high rate of benign idiopathic paraproteinemia, analogous to human MGUS. Secondarily, we recently demonstrated that chronic intermittent hypoxia (CIH), a feature of sleep apnea, allows for the engraftment of malignant plasma cells in disease resistant C57BL6/J mice. To identify potential susceptibility pathways in the two models, we used bulk RNA‐sequencing to quantify differential gene expression in KaLwRij vs. C57BLJ/6 and CIH‐exposed C57BL6/J vs. normoxic C57BL6/J. Genes were considered significant if they had an adjusted p‐value of less than 0.05 and a log2‐fold change of less than ‐1 or greater than 1. We identified 400 significant genes for KaLwRij and 69 significant genes for CIH. Significant genes were assessed for overlap, resulting in 31 duplicates. The KaLwRij and CIH mice share 31 genes that are upregulated in comparison to normoxic C57BL6/J control mice. These results provide potential mechanistic targets to prevent the terminal engraftment of malignant plasma cells in the bone marrow. In future studies, we will use single‐cell RNA sequencing data to determine which cell populations reflect the upregulation of the 31 shared genes to understand how the bone marrow microenvironment is altered in the KaLwRij and CIH mice to enhance MM proliferation.