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

Purpose: We examined how transcriptional state changes relate to clonal selection as BRAF inhibitor resistance develops in BRAF-mutated myeloma. Methods: To this end we generated three single-cell clones from U266, a BRAFK601N -mutated myeloma cell line and DP6- a BRAFV600E myeloma cell line. All three U266 and DP6 clones were subjected to long-term dabrafenib treatment at their established IC50 doses (U266: 10uM, DP6 1nM). Bulk RNA-seq was performed before treatment, day 7, day 14, day 42 and at time of resistance. Results: Transcriptional adaptation after seven days was homogeneous for all clones, but was different across both cell lines. Oxidative phosphorylation (OxPhos) emerged as the most consistently enriched signaling pathway in persistent cells from both cell lines as compared to baseline. Conclusions: BRAF inhibition in BRAF-mutated myeloma cells leads to transcriptional reprogramming with induction of OxPhos-related genes within a brief period of time. Serial transcriptional profiling by bulk RNA-seq of three single cell-clones from two myeloma cell lines undergoing dabrafenib treatment.