Dysregulation of the ALDH1A3/PML-RARα axis promotes the progression of acute promyelocytic leukemia.

Dysfunction of the retinoic acid (RA) signaling pathway, which is mediated by the formation of the PML-RARA fusion gene, plays a central role in the pathogenesis of acute promyelocytic leukemia (APL). The activation of this pathway depends on the binding of the ligand RA to RA receptors (RARs). Members of aldehyde dehydrogenase (ALDH) family are key enzymes responsible for the biosynthesis of endogenous RA and are highly enriched in various cancer stem cell subpopulations; however, their specific contributions to APL pathogenesis remain poorly understood. In this study, we demonstrate that the expression of aldehyde dehydrogenase family member 1A3 (ALDH1A3) is negatively correlated with APL progression. Through DNA pull-down assays, liquid chromatography-tandem mass spectrometry (LC‒MS/MS) analysis, chromatin immunoprecipitation (ChIP), dual-luciferase reporter assays and electrophoretic mobility shift assay (EMSA), we show that ALDH1A3 cooperates with the transcription factor Myc-associated zinc finger protein (MAZ) to transcriptionally repress PML-RARα expression. Furthermore, EMSA and methylated DNA immunoprecipitation (MeDIP) analyses reveal that PML-RARα increases methylation of the ALDH1A3 promoter, thereby suppressing its expression in APL patients. This reciprocal inhibitory relationship is correlated with clinical remission in APL. Integrated RNA sequencing (RNA-seq) and Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq) analyses indicate that ALDH1A3 overexpression is associated with increased chromatin accessibility and the upregulation of genes involved in cellular differentiation. Notably, demethylation therapy induced sustained complete remission in patients with refractory and recurrent APL during experimental treatment. Our findings underscore the critical role of ALDH1A3 in leukemogenesis and highlight its potential as a therapeutic target in APL.