Bone Marrow Stroma-induced Transcriptome and Regulome Signatures of Multiple Myeloma [ATAC-seq]

Multiple myeloma (MM) is a hematological cancer with inevitable drug resistance. MM cells interacting with bone marrow stromal cells (BMSCs) undergo substantial changes in transcriptome and develop de novo drug resistance. As a critical component in transcriptional regulation, how chromatin landscape is transformed in MM cells and regulates the transcriptional response to BMSCs remains elusive. We profiled transcriptome and regulome for MM cells using a transwell coculture system with BMSCs. The transcriptome and regulome of MM cells from the upper transwell resembled MM cells coexisting with BMSCs from the lower chamber but were distinctive to monoculture. BMSC-induced genes were enriched in JAK2/STAT3 signaling pathway, unfolded protein stress, signatures of early plasma cells, and response to proteasome inhibitors. Genes with accessibility increased at multiple regulatory sites were preferentially induced by BMSCs and enriched in response to drug and unfavorable prognostic markers from several MM patient cohorts. We proposed JUNB and ATF4::CEBPß as candidate transcription factors (TFs) that modulated the BMSC-induced transformation of regulome linked to the response to external stimuli. Together, we characterized BMSC-induced transcriptome and regulome signatures of MM cells and prioritized TFs for future study to depict epigenetic mechanisms of BMSC-induced drug resistance in MM. Overall design: To define BM stroma-induced transcriptome and regulome signatures of MM cells, we utilized an in vitro transwell coculture system, where MM cells (MM.1S or RPMI8226) resided in both the upper transwell and the lower chamber where adhesive BMSCs (HS5) co-existed. We profiled transcriptome by RNA-Seq and regulome by Omni-ATAC for MM cells in the upper transwel, MM cells in the lower chamber, and MM cells in monoculture.