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<p>The 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 <i>FGFR3</i> 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 <i>FGFR3</i> 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 vitr<i>o</i> 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.</p><p></p>

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Activating RARβ to overcome immunomodulatory drug resistance in t(4;14) human myeloma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月30日

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  • Ling Zhong,
  • Qiang Wang,
  • Miao Xian,
  • Jianfei Qian,
  • Chuanchao Zhang,
  • Wei Wu,
  • Qi Guo,
  • Yufei Zhang,
  • Rui Duan,
  • Youli Zu,
  • Sunil Mathur,
  • Robert Z. Orlowski,
  • Fenghuang Zhan,
  • Qing Yi

摘要

The 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.