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<p>All-trans retinoic acid (ATRA), a bioactive vitamin A derivative, regulates cellular differentiation by activating retinoic acid receptors (RARs). While ATRA has revolutionised acute promyelocytic leukaemia (APL) treatment, its efficacy in non-APL acute myeloid leukaemia (AML) remains limited due to intrinsic resistance mechanisms, including aberrant epigenetic states and signalling pathways. This review summarises recent mechanistic and translational advances in ATRA-based combination therapies that target differentiation blockade. We focus on the interplay between retinoic acid signalling, chromatin regulation, cell cycle control, and apoptosis, with a particular emphasis on AML. Epigenetic regulators, including the lysine-specific demethylase LSD1 (KDM1A) and the acetyltransferase GCN5 (KAT2A), together with dysregulated cell cycle control and oncogenic signalling, including Fms-like tyrosine kinase 3 (FLT3) and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR), sustain proliferation and block differentiation. Targeting these pathways with specific inhibitors synergises with ATRA to restore myeloid maturation, induce cell cycle arrest, and promote apoptosis. Future studies should identify predictive biomarkers for patient stratification to translate these synergistic concepts into clinical benefit.</p>

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Revisiting retinoic acid in AML therapy: mechanisms of action and rational combination strategies

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月2日

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  • Setenay Gupse Özcan,
  • Clara Stanko,
  • Lukasz Szymanski,
  • Martin Fischer,
  • Annamaria Brioli,
  • Arthur Zelent,
  • Tino Schenk

摘要

All-trans retinoic acid (ATRA), a bioactive vitamin A derivative, regulates cellular differentiation by activating retinoic acid receptors (RARs). While ATRA has revolutionised acute promyelocytic leukaemia (APL) treatment, its efficacy in non-APL acute myeloid leukaemia (AML) remains limited due to intrinsic resistance mechanisms, including aberrant epigenetic states and signalling pathways. This review summarises recent mechanistic and translational advances in ATRA-based combination therapies that target differentiation blockade. We focus on the interplay between retinoic acid signalling, chromatin regulation, cell cycle control, and apoptosis, with a particular emphasis on AML. Epigenetic regulators, including the lysine-specific demethylase LSD1 (KDM1A) and the acetyltransferase GCN5 (KAT2A), together with dysregulated cell cycle control and oncogenic signalling, including Fms-like tyrosine kinase 3 (FLT3) and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR), sustain proliferation and block differentiation. Targeting these pathways with specific inhibitors synergises with ATRA to restore myeloid maturation, induce cell cycle arrest, and promote apoptosis. Future studies should identify predictive biomarkers for patient stratification to translate these synergistic concepts into clinical benefit.