Single-cell multiomic mapping of genetic predisposition to childhood B-cell acute lymphoblastic leukemia.
This preprint reports a single-cell multiomic variant-to-function map of inherited childhood B-ALL risk, identifies 34 high-confidence susceptibility genes, and functionally validates a risk allele associated with selective ELK3 upregulation.
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This preprint reports a single-cell multiomic variant-to-function map of inherited childhood B-ALL risk, identifies 34 high-confidence susceptibility genes, and functionally validates a risk allele associated with selective ELK3 upregulation.
Research significance
The evidence links inherited regulatory variation, including an ELK3-upregulating allele, to B-cell progenitor programs associated with B-ALL predisposition; it remains an inference that targeting ELK3-related pathways or these regulatory programs could enable prevention, risk-adapted surveillance, or therapy.
Source 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.