Uncovering the regulatory landscape of early human B cell lymphopoiesis and its implications in the pathogenesis of B-ALL

Dysregulation of early B cell lymphopoiesis—the process guiding cellular immunity development—can lead to malignancy, making it crucial to understand its regulatory mechanisms. We generated a multiomics resource comprising paired chromatin accessibility and gene expression profiles across eight human B cell precursor populations, providing a detailed characterization of early human B cell development. Integrative analysis revealed highly cell type–specific regulatory elements and enabled the reconstruction of the gene regulatory network governing differentiation. We identified putative candidate regulons, such as ELK3, enriched in pro–B cells and potentially involved in cell cycle progression. Regulons from bulk data were projected onto single-cell data, validating their activity and refining the regulatory landscape. This resource enabled identification of active regulatory programs and transformation-associated states in B cell acute lymphoblastic leukemia. The publicly available atlas provides a valuable resource for understanding B cell development and disease, supporting future efforts to decode regulatory programs in immunity and hematologic malignancies.