Single-cell multiomic mapping of genetic predisposition to childhood B-cell acute lymphoblastic leukemia
Lee, A. J.; Neehus, A.-L.; Wahlster, L.; Agarwal, G.; Weng, C.; Zhang, A.; Liu, T.; Shelton, S.; Ye, T.; Volpe, L. d.; Cohn, O.; Poeschla, M.; King, E.; Ha, S. A.; Turvey, A. K.; Chiang, C. W. K.; Wiemels, J. L.; de Smith, A. J.; Sankaran, V. G.
Show abstract
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.
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