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<p>NPM1 mutation (NPM1c)-driven acute myeloid leukemia (AML) is characterized by the sequestration of nuclear proteins and chromatin hijacking. Current treatment strategies targeting NPM1c AML are often indirect, which might lead to toxicity and resistance. In this study, we developed an allele-specific siRNA that selectively silences NPM1c while preserving the function of wild-type NPM1. This approach inhibited proliferation and promoted myeloid differentiation in NPM1-mutated AML cells in vitro. Notably, the systemic delivery of chemically optimized siNPM1c via lipid nanoparticles (LNPs) significantly reduced leukemogenesis, and enhanced the therapeutic efficacy of the menin inhibitor revumenib and overcame its resistance in vivo. Mechanistically, NPM1c recruits KAT7 and p300, driving leukemogenic transcription and establishing a pathogenic acetylome and open chromatin state. KAT7 recruitment is crucial for the retention of this complex on chromatin. Targeting NPM1c with siRNA disrupts this interaction, reverses the oncogenic epigenetic landscape, and suppresses transcription. Our findings demonstrate that silencing NPM1c effectively suppresses AML by dismantling a pathogenic KAT7/p300-dependent acetylome, highlighting the potential of LNP‑delivered siNPM1c as a promising therapeutic strategy, either as a monotherapy or in combination with menin inhibition.</p>

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Small interfering RNA-mediated silencing of mutant NPM1 suppresses acute myeloid leukemia via reversing KAT7 and p300-mediated histone acetylation

  • 期刊论文

  • 发表日期：

    2026年6月26日

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  • Yongqiang Hou,
  • Yunzhi Xing,
  • Chunjie Chen,
  • Dongxue Su,
  • Zhien Zhou,
  • Yi Ye,
  • Zhangjian Lai,
  • Zhixian Peng,
  • Hongxi Cai,
  • Min Sun,
  • Yue Liu,
  • Bingying Yang,
  • Haitao Huang,
  • Zhe Li,
  • Jinhuan Li,
  • Junhong Li,
  • Huan Gao,
  • Jiaxin Li,
  • Hao Zhao,
  • Yiran Shi,
  • Qinghua Chen,
  • Jun Long,
  • Jiong Hu,
  • Dawang Zhou,
  • Lanfen Chen

摘要

NPM1 mutation (NPM1c)-driven acute myeloid leukemia (AML) is characterized by the sequestration of nuclear proteins and chromatin hijacking. Current treatment strategies targeting NPM1c AML are often indirect, which might lead to toxicity and resistance. In this study, we developed an allele-specific siRNA that selectively silences NPM1c while preserving the function of wild-type NPM1. This approach inhibited proliferation and promoted myeloid differentiation in NPM1-mutated AML cells in vitro. Notably, the systemic delivery of chemically optimized siNPM1c via lipid nanoparticles (LNPs) significantly reduced leukemogenesis, and enhanced the therapeutic efficacy of the menin inhibitor revumenib and overcame its resistance in vivo. Mechanistically, NPM1c recruits KAT7 and p300, driving leukemogenic transcription and establishing a pathogenic acetylome and open chromatin state. KAT7 recruitment is crucial for the retention of this complex on chromatin. Targeting NPM1c with siRNA disrupts this interaction, reverses the oncogenic epigenetic landscape, and suppresses transcription. Our findings demonstrate that silencing NPM1c effectively suppresses AML by dismantling a pathogenic KAT7/p300-dependent acetylome, highlighting the potential of LNP‑delivered siNPM1c as a promising therapeutic strategy, either as a monotherapy or in combination with menin inhibition.