Single-cell chromatin profiling reveals relapse-related priming in pediatric acute myeloid leukemia

Relapse remains the leading cause of treatment failure and mortality in pediatric acute myeloid leukemia (pAML), yet the early molecular features underlying relapse susceptibility remain poorly understood. Here, we leveraged our previously generated single-cell chromatin accessibility dataset comprising 177,500 cells from 16 diagnostic pAML samples with long-term clinical outcome data, spanning t(8;21), inv(16), and FLT3-ITD subtypes and stratified into relapse (RPS) and non-relapsed (NRPS) cases. We show that RPS patients harbor relapse-associated chromatin accessibility signatures already detectable at diagnosis across multiple molecular subtypes. These patients display heightened innate immune and inflammatory activation and expansion of HSC/MPP-like leukemic progenitors with stem cell-like regulatory features. Motif enrichment analyses identify AP-1 family members, together with RUNX1, SPI1, and ETS factors, as central regulators shaping the relapse-associated epigenetic state. Elevated expression of these regulators predicts inferior survival across independent AML cohorts. Collectively, these findings suggest that early epigenetic priming of innate immune and inflammatory programs is associated with a relapse-prone state and highlight this core transcriptional network as a candidate biomarker framework in pAML.