PNNL

Abstract

Multiple myeloma (MM) is a highly refractory hematological cancer for which targeted immunotherapy has shown promise but remains hindered by the challenge of identifying specific yet broadly representative tumor markers. We analyzed 53 bone marrow (BM) aspirates from 41 MM patients using an unbiased, high-throughput pipeline for therapeutic target discovery via single-cell transcriptomic profiling, yielding 38 MM marker genes encoding cell-surface proteins and fifteen encoding intracellular proteins. We highlight 20 candidate genes not yet under clinical study, eleven of which are previously uncharacterized for therapeutic potential. We cross-validated our findings using bulk RNA-sequencing, flow cytometry, and proteomic mass spectrometry of MM cell lines and patient BM, finding high overall concordance across data types. Independent discovery using bulk RNA-sequencing reiterated top candidates, further affirming the ability of single cell transcriptomics to accurately capture marker expression despite limitations in sample size or sequencing depth. We further examined target dynamics and heterogeneity using both transcriptomic and immuno-imaging methods. In summary, we present a robust and broadly applicable strategy for identifying tumor markers to better inform the development of targeted cancer therapy.