Targeting dysregulated epigenetic and transcription factor networks in -rearranged AML using iPSC models.

chromosomal rearrangements (r) are frequent in pediatric acute myeloid leukemia (AML) and are associated with poor prognosis. The gene encodes a histone lysine methyltransferase responsible for maintaining active chromatin marks (H3K4me3) at gene promoters and enhancers. r lead to the formation of oncogenic fusion proteins with over 70 potential partners, disrupting normal hematopoiesis and driving leukemogenesis. Among these, ::, a fusion of and , is one of the most prevalent in AML. Disruption of the epigenome is a hallmark of AML, with recurrent abnormalities in epigenetic regulators. These alterations often occur early as disease-initiating events, making epigenetic-targeted therapeutics a promising avenue for treatment. Induced pluripotent stem cells (iPSCs) have emerged as faithful models of human AML pathogenesis, recapitulating the underlying genomic lesions and epigenetic profiles. We investigated transcriptional regulation of hematopoietic development using iPSCs derived from a patient with AML with the :: rearrangement. Our analysis identified key transcriptional activators and repressors that contribute to the altered regulatory landscape in :: AML. Further analysis of chromatin immunoprecipitation sequencing data indicated that a significant subset of genes, whose expression was downregulated in AML iPSC-derived hematopoietic stem and progenitor cells (AML-HSPCs), were direct targets of Polycomb Repressive Complex 2 (PRC2). Treatment with the dual EZH1/2 inhibitor UNC1999 and 5-azacytidine reactivated these PRC2 target genes, specifically in AML-HSPCs, toward normal gene expression patterns. These findings suggest that targeting Polycomb repression offers a promising epigenetic strategy for improving outcomes in rearranged AML.