The spatial and multi-omic landscape of Down syndrome leukemogenesis: moving beyond cellular heterogeneity.

Down syndrome (DS) confers a developmentally rooted predisposition to both myeloid and lymphoid leukemias, particularly myeloid leukemia associated with DS (ML-DS) and acute lymphoblastic leukemia associated with DS (ALL-DS). While trisomy 21-driven gene dosage imbalance is central to this risk, DS leukemogenesis cannot be fully explained by recurrent mutations alone; it reflects a dynamic interplay between altered hematopoietic development, cell-intrinsic programs, and tissue microenvironmental cues. In this perspective, we argue that the field should move beyond cataloging cellular heterogeneity and adopt a topographic, multi-omic framework of DS leukemogenesis. We discuss how fetal niche biology shapes pre-leukemic evolution in ML-DS, including the developmental context of GATA1-mutant clones, and how therapy-driven bottlenecks may promote persistence of spatially protected residual disease in ALL-DS. We further highlight the translational potential of integrating spatially resolved transcriptomics with single-cell and protein-aware multi-omics to identify compartment-specific signaling programs and clinically actionable vulnerabilities. A spatially informed model of DS leukemia may improve biological stratification, clarify mechanisms of relapse and toxicity, and support the development of more effective and less toxic therapeutic strategies.