Transcriptional adaptation and enhancer rewiring promote metabolic resistance in BRAFmutated multiple myeloma (scRNA-seq). Transcriptional adaptation and enhancer rewiring promote metabolic resistance in BRAFmutated multiple myeloma (scRNA-seq)

Purpose: We here applied single-cell RNA sequencing of circulating MM cells from primary MM patients to perform transcriptional profiling of myeloma cells and study emerging resistance mechanisms in real-time. Methods: A total of 1509 single CD138+/CD38+ myeloma and normal plasma cells from three patients and one normal donor were examined by full-length single-cell RNA sequencing. Results: Quality filtering resulted in the retention of 1153 cells with an average of 4836 genes detected per cell. Rapid transcriptional adaptation was observed in the presence of BRAF/MEK inhibitor treatment. Conclusions: Inhibition of the BRAF/MEK pathway in myeloma patients induces cellular adaptation accompanied by metabolic resistance and preferential transcriptional activation of OxPhos. Overall design: Single-cell RNA sequencing of 1509 CD138+/CD38+ myeloma and normal plasma cells from three patients and a normal donor before and while undergoing dabrafenib/ treatment *** Raw data not submitted to GEO due to patient privacy concerns ***