ATRA Resistance in Acute Promyelocytic Leukemia: Mechanisms Unveiled, Therapies Reimagined

All-trans retinoic acid (ATRA) has dramatically improved outcomes for patients with acute promyelocytic leukemia (APL), turning a once fatal disease into one that is often curable. Yet, resistance to ATRA remains a significant challenge, especially in relapsed cases. This review outlines key mechanisms contributing to resistance, including mutations in the RARA ligand-binding domain, disruption of promyelocytic leukemia (PML) nuclear bodies (NBs), epigenetic repression, impaired autophagy, altered metabolism, and uncommon retinoic acid receptor (RAR) fusion variants. We also examine emerging therapeutic strategies designed to overcome these barriers, such as tamibarotene, arsenic-based regimens, FLT3 and BCL2 inhibitors, and epigenetic or immune-targeted treatments. Understanding these mechanisms is essential to guide more tailored therapies for APL and related myeloid malignancies.