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.