Epigenetic regulation plays a critical role in numerous biological processes. The overarching goal of my laboratory is to understand epigenetic mechanisms of drug resistance of hematological cancers in the bone marrow (BM) microenvironment. I have over 12 years of research experience on transcription regulation of chromatin regulators in immune cells, embryonic stem cells, and cancer cells. This proposal is to investigate the transcription-regulatory role of a leucine-zipper TF C/EBPβ in promoting de novo drug resistance of Multiple Myeloma (MM) in the BM microenvironment. MM is a disease caused by malignant plasma B cells mainly proliferating in the BM. It is incurable largely because of the emergence of drug resistance after treatments. One important contribution to drug resistance stems from the protective effect of the BM microenvironment, which includes growth promoting soluble factors and physical interaction with cellular components such as stromal cells and osteoblasts. The emergence of de novo drug resistance occurs in a short timeframe and is reversible, suggesting epigenetic mechanisms as an important contributor. However, the identities and mechanisms of chromatin regulators contributing to de novo drug resistance of MM in the BM microenvironment remain largely unexplored. Our preliminary results indicated C/EBPβ as a key transcription regulator of target genes of signaling pathways activated by BM stromal cells. The BM stromal cells induced a genome-wide reprogramming in gene expression (transcriptome) and chromatin accessibility (regulome) of MM cells, turned out being mainly driven by soluble factors. Integrative analysis with ENCODE genomic binding data indicated C/EBPβ as a major contributor to the BM stromal cellinduced transformation of transcriptome and regulome. As C/EBPβ- overexpression protects MM cells from IMiD compounds, our preliminary results defined C/EBPβ as a promising and new research subject to understand epigenetic mechanisms for the emergence of de novo drug resistance in MM. We hypothesize that C/EBPβ contributes to soluble factor-mediated drug resistance by transcriptionally regulating target genes of growth-promoting signaling pathways activated by BM stromal cells through