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In this study, we conducted a systematic analysis of recurrent somatic non\u2010coding single nucleotide variants (SNVs) in pediatric B\u2010cell precursor (BCP) ALL. We leveraged whole genome sequencing (WGS) data from 345 pediatric BCP ALL cases, representing all major genetic subtypes and identified 346 mutational hotspots that harbored somatic SNVs in at least three cases. Through the integration of paired RNA sequencing along with published ChIP\u2010seq and ATAC\u2010seq data, we found 128 non\u2010coding hotspots associated with differentially expressed genes nearby, which were enriched for cis\u2010regulatory elements, demonstrating the effectiveness of multi\u2010omics integration in distinguishing pathogenic mutations from passengers. We identified one mutational hotspot that was associated with increased expression of the leukemia\u2010associated gene <jats:italic>NRAS<\/jats:italic> in three primary ALLs. Micro\u2010C analysis in the leukemia cell line demonstrated interactions between the hotspot region and <jats:italic>NRAS<\/jats:italic> regulatory elements. Dual luciferase assays indicated that the mutations disrupted regulatory interactions and CRISPR\u2010mediated deletion of the region significantly upregulated <jats:italic>NRAS<\/jats:italic>, confirming the hypothesized regulatory link. Altogether, we provide new insights into the functional roles of non\u2010coding mutations in leukemia.<\/jats:p>","DOI":"10.1002\/gcc.70045","type":"journal-article","created":{"date-parts":[[2025,3,30]],"date-time":"2025-03-30T09:28:10Z","timestamp":1743326890000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Discovery of Cis\u2010Regulatory Mechanisms via Non\u2010Coding Mutations in Acute Lymphoblastic Leukemia"],"prefix":"10.1002","volume":"64","author":[{"given":"Efe","family":"Ayd\u0131n","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine, Division of Clinical Genetics Lund University  Lund Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eleanor L.","family":"Woodward","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Division of Clinical Genetics Lund University  Lund 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