DOI RECORD
Integrated Single-Cell and Cross-Species Analysis Reveals CMP Vulnerability and SMYD3 as a Novel Epigenetic Biomarker in Acute Myeloid Leukemia
Abstract
Abstract Acute myeloid leukemia (AML) is a highly heterogeneous disease driven by blocked hematopoietic differentiation and dysregulated epigenetic control, yet its cell-level mutational landscape remains incompletely defined. Here, we analyzed single-cell RNA-sequencing data from human AML patients and a mouse Ezh2/Nras G12D mutation model to map mutation susceptibility across hematopoietic cell types. By integrating seven mutation-related biological metrics, we identified common myeloid progenitors (CMPs) and dendritic cells (DCs) as the two cell populations with the highest predicted mutation risk. Cross-species comparison revealed four homologous genes— Smyd3 , Etv6 , H2-D1 , and Hspa8 —shared between mutation-prone human cell types and their differentially expressed mouse counterparts. Pseudotime analysis showed that Ezh2 loss and the Nras G12D mutation disrupted normal hematopoietic differentiation trajectories and drove premature activation of these four genes during early differentiation. External cohort validation further supported SMYD3 , ETV6 , and HSPA8 as candidate AML biomarkers. These findings identify CMPs and DCs as key mutation-susceptible populations and nominate SMYD3 , ETV6 , and HSPA8 as candidate biomarkers, providing single-cell level insight into AML pathogenesis.