Abstract
Simple SummaryThe bone marrow (BM) microenvironment provides a protective sanctuary for multiple myeloma (MM) against therapeutic agents. MM cells interact with BM stromal cells (BMSCs) and the interaction is sufficient to confer de novo multi-drug resistance with epigenetic mechanisms as one of the contributors yet to be elucidated. We profiled genome-wide landscapes of gene expression (transcriptome) and chromatin accessibility (regulome) for MM cells interacting with BMSCs and characterized the induced signatures. We evaluated the contributions from soluble factors derived from BMSCs and compared these results to physical adhesion to the BMSC-induced changes in the transcriptome and regulome. The multi-omics approach further identified candidate transcription factors that regulate the BMSC-induced transcriptome through modulating the regulome, which may lead to promising novel therapeutic targets for the treatment of MM.Multiple myeloma (MM) is a hematological cancer with inevitable drug resistance. MM cells interacting with bone marrow stromal cells (BMSCs) undergo substantial changes in the transcriptome and develop de novo multi-drug resistance. As a critical component in transcriptional regulation, how the chromatin landscape is transformed in MM cells exposed to BMSCs and contributes to the transcriptional response to BMSCs remains elusive. We profiled the 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 that coexisted with BMSCs from the lower chamber but were distinctive to monoculture. BMSC-induced genes were enriched in the JAK2/STAT3 signaling pathway, unfolded protein stress, signatures of early plasma cells, and response to proteasome inhibitors. Genes with increasing accessibility at multiple regulatory sites were preferentially induced by BMSCs; these genes were enriched in functions linked to responses to drugs and unfavorable clinic outcomes. We proposed JUNB and ATF4::CEBPβ as candidate transcription factors (TFs) that modulate the BMSC-induced transformation of the regulome linked to the transcriptional response. Together, we characterized the BMSC-induced transcriptome and regulome signatures of MM cells to facilitate research on epigenetic mechanisms of BMSC-induced multi-drug resistance in MM.
Highlights
There was an estimated 34,920 new cases of Multiple Myeloma (MM) and 12,410 deaths in the United States for 2021 [1]
By taking peaks not differentially accessible as the background, we identified DNA motifs corresponding to JUNB and the heterodimer of ATF::CEBP for peaks showing an increase in accessibility (Figure 6B); for completeness, we listed the motifs for peaks showing a decrease in accessibility (Supplementary Figure S6A)
Soluble factors secreted from bone marrow stromal cells (BMSCs) and physical adhesion to BMSCs activate a panel of signaling pathways in MM cells, resulting in transcriptome reprogramming leading to drug resistance [8,30]
Summary
There was an estimated 34,920 new cases of Multiple Myeloma (MM) and 12,410 deaths in the United States for 2021 [1]. The malignant plasma cells interact with cellular components of bone marrow, such as bone marrow stromal cells (BMSCs), and non-cellular components, such as soluble factors and extracellular matrices; the interaction is sufficient to cause drug resistance independent from genetic mutations [2–5]. This de novo drug resistance protects MM from chemotherapy, contributes to minimal residual disease (MRD), and increases the chance of acquired drug resistance [6]. Investigating the mechanisms of BM-mediated drug resistance helps to define new therapeutic targets to pursue for drug development The goal of this development is to increase the efficacy of combination strategies and delay the emergence of drug resistance associated with standard-of-care agents used to treat MM patients
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