GSE193695
Identification of a drug-response gene in multiple myeloma through longitudinal single-cell transcriptome sequencing.
Multiple myeloma (MM) is a life-threatening, chronic, and incurable hematological malignancy, which is characterized by clonal proliferation of malignant plasma cells. Despite recent therapeutic advances, relapse is very common during a long-term exposure to drugs with no therapeutic effects. Here, we conducted longitudinal single-cell transcriptome sequencing (scRNA-seq) of bone marrow cells from a single patient with relapsed and refractory MM, who had been treated with multiple anti-myeloma drugs, and found five UMAP subclusters (clusters 0-4) of MM cells, which appeared and/or disappeared in response to the therapeutic pressure. A small cell cluster 3, which emerged during lenalidomide treatment and disappeared after the addition of a proteasome inhibitor (PI), ixazomib. Among the differentially expressed genes in cluster 3, we found a candidate drug-response gene; pellino E3 ubiquitin protein ligase family member 2 (PELI2), which is responsible for PI-induced cell death in in vitro cell cultured assay. Kaplan-Meier survival analysis of datasets from pan-cancer prognostic database revealed that higher expression of PELI2 is associated with better prognosis. The data of this study suggest that PELI2 is a predictive biomarker of the PI response in patients with MM. Our integrated strategy combining longitudinal scRNA-seq analysis, in vitro functional assay, and database analysis would facilitate the understanding of clonal dynamics of MM in response to anti-myeloma drugs and identification of drug response genes. Overall design: Longitudinal scRNA-seq of myeloma cells from a patient with relapse and refractory disease.