Reawakening Differentiation Therapy in Acute Myeloid Leukemia: A Comprehensive Review of ATRA-Based Combination Strategies.

(1)

Background

All-trans retinoic acid (ATRA) has transformed the treatment of acute promyelocytic leukemia (APL) by inducing terminal myeloid differentiation. However, its efficacy in non-APL acute myeloid leukemia (AML) is limited. Exploring combination strategies that enhance ATRA-induced differentiation may broaden its therapeutic potential. (2)

Methods

A literature search of PubMed using the keywords "ATRA," "myeloid," and "differentiation inducer or enhancer" identified more than 500 published papers as of November 2025. Pre-clinical and clinical studies were reviewed, with a focus on mechanisms, combination partners, and translational relevance. (3)

Results

Clinical evidence confirms that ATRA combined with arsenic trioxide or epigenetic modulators achieves high remission rates in APL and selected AML subtypes. Pre-clinical studies show synergistic differentiation effects when ATRA is combined with CDK and kinase inhibitors, nucleotide synthesis inhibitors, DNA-damaging agents, Bcl-2/MDM2 inhibitors, proteasome inhibitors, cytokines, glycosylation modifiers, natural products, and antibiotic-derived compounds. Mechanistically, these combinations modulate key signaling pathways (MAPK, Akt, JAK/STAT), stabilize RARα, remodel chromatin, and perturb nucleotide metabolism. Although translation to non-APL AML remains limited, these findings provide a rational basis for future clinical trials. (4) ATRA-based combination therapies represent a promising strategy to extend differentiation therapy beyond APL. This review, authored solely by the investigator, highlights molecular targets and potential enhancers warranting further clinical evaluation in AML.