Single-cell multiomic mapping of genetic predisposition to childhood B-cell acute lymphoblastic leukemia

Inherited genetic variation substantially increases the risk for developing childhood B-cell acute lymphoblastic leukemia (B-ALL), the most common cancer in children, yet the underlying mechanisms remain poorly understood. To address this limitation, we employ a single-cell multiomic framework to functionally dissect common regulatory variants associated with B-ALL risk. Coupling this multiomic analysis with assessment of allelic skews in chromatin accessibility, we reveal the impact of risk alleles and disruptions in transcription factor networks specific to B-cell progenitors, thereby providing mechanistic insights into altered regulatory programs underlying B-ALL predisposition. By constructing long-range variant-to-target gene maps, we identify 34 high-confidence B-ALL susceptibility genes. Among these, we uncover and functionally validate a risk allele that selectively upregulates expression of ELK3, a previously unrecognized regulator of B-cell development and leukemogenesis. Together, these findings establish a comprehensive variant-to-function map of cell state-specific regulatory disruptions underlying inherited predisposition to B-ALL and define new risk mechanisms, which could pave the way for future targeted prevention approaches.