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<p>Nucleophosmin-1 (NPM1) is a nucleolar chaperone protein frequently mutated in acute myeloid leukemia (AML). ARF and Sentrin/SUMO Specific Peptidase 3 (SENP3) control NPM1 functions through dynamic SUMOylation/de-SUMOylation. Mutated NPM1 is an oncoprotein that exhibits an aberrant cytoplasmic localization (NPM1c) and disrupts PML/P53 signaling. Studies reported increased survival of patients with NPM1c AML when retinoic acid (RA) was added to chemotherapy or hypomethylating agents. Ex vivo, RA initiates NPM1c degradation, P53 activation and cell death. Yet, the molecular mechanisms involved remain elusive. Here we show that in NPM1c AML cell lines or patients’ blasts, NPM1c-triggered mitochondrial dysfunction and oxidative stress drive NPM1c stabilization through SENP3 upregulation. RA decreases mitochondrial ROS production, driving degradation of SENP3, ARF stabilization, PML-dependent NPM1c hyperSUMOylation followed by RNF4-dependent ubiquitination and degradation. Thus, the feedback loop stabilizing NPM1c protein can be interrupted by RA-triggered enhanced mitochondrial fitness, mechanistically explaining the benefit of RA in chemotherapy or hypomethylating agents-treated AMLs.</p>

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Retinoic acid disrupts an NPM1c/ROS/SENP3/ARF oncogenic axis in acute myeloid leukemia

  • 期刊论文

  • 发表日期：

    2025年8月26日

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  • Rita Hleihel,
  • Hala Skayneh,
  • Hsin-Chieh Wu,
  • Maguy Hamie,
  • Abdallah Kurdi,
  • Jana Dakour,
  • Charbel Machaalani,
  • Marwan El-Sabban,
  • Hugues de Thé,
  • Ali Bazarbachi,
  • Hiba El Hajj

摘要

Nucleophosmin-1 (NPM1) is a nucleolar chaperone protein frequently mutated in acute myeloid leukemia (AML). ARF and Sentrin/SUMO Specific Peptidase 3 (SENP3) control NPM1 functions through dynamic SUMOylation/de-SUMOylation. Mutated NPM1 is an oncoprotein that exhibits an aberrant cytoplasmic localization (NPM1c) and disrupts PML/P53 signaling. Studies reported increased survival of patients with NPM1c AML when retinoic acid (RA) was added to chemotherapy or hypomethylating agents. Ex vivo, RA initiates NPM1c degradation, P53 activation and cell death. Yet, the molecular mechanisms involved remain elusive. Here we show that in NPM1c AML cell lines or patients’ blasts, NPM1c-triggered mitochondrial dysfunction and oxidative stress drive NPM1c stabilization through SENP3 upregulation. RA decreases mitochondrial ROS production, driving degradation of SENP3, ARF stabilization, PML-dependent NPM1c hyperSUMOylation followed by RNF4-dependent ubiquitination and degradation. Thus, the feedback loop stabilizing NPM1c protein can be interrupted by RA-triggered enhanced mitochondrial fitness, mechanistically explaining the benefit of RA in chemotherapy or hypomethylating agents-treated AMLs.