GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE304nnn/GSE304473/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE304473GEOGSEfalseActivating RARβ to overcome immunomodulatory drug resistance in t(4;14) human myelomaThe t(4;14) translocation is a high-risk cytogenetic abnormality in multiple myeloma (MM) that results in overexpression of fibroblast growth factor receptor 3 (FGFR3) and enhanced MM proliferation, leading to poor prognosis. Herein, we carried out a high-throughput screen on 1855 Food and Drug Administration (FDA)-approved pharmaceuticals and identified all-trans retinoic acid (ATRA), which alone has no anti-MM effect, as a potent drug that enhances the cytotoxic effects of immunomodulatory drugs (IMiDs) in t(4;14) MM cells. Mechanistically, ATRA activates retinoic acid receptor β (RARβ), which then binds to retinoic acid response elements in the FGFR3 promoter. IMiDs enhanced nuclear translocation of histone deacetylase (HDAC)-5 and 3 by reducing HDAC5 Ser498 phosphorylation levels. RARβ, HDAC5 and HDAC3 formed a co-repressor complex that reduced chromatin accessibility and H3K27 acetylation in FGFR3 promoter, FGFR3 expression, and suppressed phosphoinositide 3-kinase/AKT signaling pathways, leading to more MM cell death. Similarly, CD2314, a selective RARβ agonist, sensitized and resensitized t(4;14) MM cells to IMiDs in vitro and in vivo. Thus, these findings underscore the therapeutic potential of ATRA and RARβ agonists in enhancing the efficacy of IMiD-based treatments for t(4;14) MM and offer a promising strategy to overcome IMiD resistance and improve outcomes in this high-risk subgroup.2026/07/28GSE304473GSM9151202GSM9151201GSM9151200GSM9151199GSM9151206GSM9151205GSM9151204GSM915120324676304473Homo sapiens