Transcriptome Analysis Identifies Functional and Prognostic Hypoxia-Associated Genes in Multiple Myeloma.

Introduction: Multiple myeloma (MM) is an incurable clonal B-cell malignancy characterized by the accumulation of neoplastic plasma cells in the bone marrow (BM). Many pieces of evidence indicate that hypoxia promotes MM progression, but the underlying mechanisms are not well known.

Methods: We analyzed gene expression profiles of 3 MM cell lines under hypoxia and the MMRF CoMMpass project. We validated the expression patterns of hypoxia-associated genes (HAGs) in CD138+ BM cells from MM patients at different stages. Single-cell RNA sequencing data were used to analyze the performance of HAGs in the BM microenvironment.

Results: We identified 17 HAGs differentially expressed in three MM cell lines under hypoxia. While in the MMRF project, we identified 92 differentially expressed HAGs in newly diagnosed MM patients. MM cell lines and the MMRF project shared 9 HAGs, including ADM, BNIP3L, EGLN1, FAM162A, HMOX1, PDK1, PLOD1, STAT5B, and TFRC. Notably, 8 of them were significantly associated with the overall survival of MM patients, and 6 were significantly associated with the MM patient survival in the first year after diagnosis. Then, hypoxia pressure scores calculated using these genes displayed significant differences between MM patients and healthy individuals. Further, we validated the expression patterns of HAGs using another cohort data and performed qRT-PCR using our own samples, and the results confirmed severe hypoxia existed in plasma cells and other cell types of the BM microenvironment of MM patients compared to healthy individuals.

Conclusion: Taken together, our findings may contribute to the treatment and prognosis prediction of MM patients.