Looking at patient-blood-derived IM-sEVs, we identified 102 potential circulating biomarkers for B-ALL subtypes (70 ETV6::RUNX1-specific, 17 TCF3::PBX1-specific, and 15 shared between them), encompassing mRNAs, lncRNAs, circRNAs, and pseudogenes. Here, PBX1 is linked to precursor B-cell acute lymphoblastic leukemia.