To characterize the genomic basis and functional context of BCP-ALL relapse, we applied a multi-omics approach on matched diagnosis and relapse samples from pediatric and adult patients (n = 50) lacking well-studied recurrent cytogenetically detectable chromosomal rearrangements BCR-ABL1, KMT2A-AFF1, ETV6-RUNX1, TCF3-PBX1. This evidence concerns the gene RUNX1 and acute lymphoblastic leukemia.