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.

doi:10.64898/2026.08.06.743308

bioRxiv · 10.64898/2026.08.06.743308

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.

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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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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.. 2026-08-07. Single-cell multiomic mapping of genetic predisposition to childhood B-cell acute lymphoblastic leukemia. https://doi.org/10.64898/2026.08.06.743308

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