https://orcid.org/0009-0007-5226-0372
Key Points
Patient-derived iPSC models of KMT2A-rearranged AML reveal transcriptional rewiring of HSPCs, driven by Polycomb-mediated silencing.
PRC2 inhibition restores epigenetic and transcriptional balance in KMT2A::MLLT3 AML, reducing the leukemic phenotype.
Abstract
KMT2A chromosomal rearrangements (KMT2A-r) are frequent in pediatric acute myeloid leukemia (AML) and are associated with poor prognosis. The KMT2A gene encodes a histone lysine methyltransferase responsible for maintaining active chromatin marks (H3K4me3) at gene promoters and enhancers. KMT2A-r lead to the formation of oncogenic KMT2A fusion proteins with over 70 potential partners, disrupting normal hematopoiesis and driving leukemogenesis. Among these, KMT2A::MLLT3, a fusion of KMT2A and MLLT3, is one of the most prevalent in AML. Disruption of the epigenome is a hallmark of AML and abnormalities in epigenetic regulators are among the most recurrent events. Lesions in epigenetic regulators are often early, disease-initiating events, making epigenetic-targeting 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 an AML patient with the KMT2A::MLLT3 rearrangement. Our analysis identified key transcriptional activators and repressors that contribute to the altered regulatory landscape in KMT2A::MLLT3 AML. Further analysis of ChIP-seq 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 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 KMT2A-r AML.
Author notes
These authors contributed equally to this work.
Shared corresponding and last authors.
Data Sharing Statement: Sequencing data are available at GEO under accession numbers GSE276955 (RNA-seq; token mbqbkeamnnyznwd) and GSE276959 (CAGE-seq; token wpohqgioxxohtut). Supplemental Table 3 summarizes all publically available datasets used in the analyses.
