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<p>Recent studies have shown that the interaction between acute myeloid leukemia (AML) and bone marrow stromal cells (BMSCs) plays a vital role in the progression of leukemia and the development of drug resistance, while the underlying mechanisms remain inconclusive. In this study, we found that AML patient-derived BMSCs exhibit a hyperinflammatory phenotype. Histone deacetylase 3 (HDAC3) in BMSCs enhances mitochondrial reactive oxygen species (ROS) production by RAB5A-mediated blockade of mitophagy. Furthermore, we confirmed that HDAC3 regulates RAB5A expression through transcription factor YY1. Excessive ROS accelerates the senescence of BMSCs and promotes the secretion of senescence-associated secretory phenotype, creating a hyperinflammatory bone marrow niche, activating the NF-κB pathway in AML cells to promote their survival and drug resistance. The inhibition of HDAC3 in BMSCs reduces the mitochondrial ROS production and thus delays BMSCs senescence. Consequently, HDAC3 inhibition in BMSCs decreases AML proliferation and synergizes with the anti-AML efficacy of venetoclax. Therefore, our study suggests that targeting HDAC3 in BMSCs may be used for the combination therapy of AML by remodeling the AML-supportive niche.</p>

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HDAC3-YY1-RAB5A axis remodels AML-supportive niche by modulating mitochondrial homeostasis in bone marrow stromal cells

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年7月7日

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  • Chao He,
  • Yue Xiong,
  • Yuqing Zeng,
  • Jianhua Feng,
  • Fuxia Yan,
  • Manqi Zhang,
  • Zhili Tan,
  • Yaling Zheng,
  • Hongbo Chen,
  • Rui Huang,
  • Fang Cheng

摘要

Recent studies have shown that the interaction between acute myeloid leukemia (AML) and bone marrow stromal cells (BMSCs) plays a vital role in the progression of leukemia and the development of drug resistance, while the underlying mechanisms remain inconclusive. In this study, we found that AML patient-derived BMSCs exhibit a hyperinflammatory phenotype. Histone deacetylase 3 (HDAC3) in BMSCs enhances mitochondrial reactive oxygen species (ROS) production by RAB5A-mediated blockade of mitophagy. Furthermore, we confirmed that HDAC3 regulates RAB5A expression through transcription factor YY1. Excessive ROS accelerates the senescence of BMSCs and promotes the secretion of senescence-associated secretory phenotype, creating a hyperinflammatory bone marrow niche, activating the NF-κB pathway in AML cells to promote their survival and drug resistance. The inhibition of HDAC3 in BMSCs reduces the mitochondrial ROS production and thus delays BMSCs senescence. Consequently, HDAC3 inhibition in BMSCs decreases AML proliferation and synergizes with the anti-AML efficacy of venetoclax. Therefore, our study suggests that targeting HDAC3 in BMSCs may be used for the combination therapy of AML by remodeling the AML-supportive niche.