{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T19:28:53Z","timestamp":1793647733586,"version":"4.5.1"},"reference-count":0,"publisher":"American Society of Hematology","license":[{"start":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T00:00:00Z","timestamp":1793577600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"abstract":"<jats:p>Relapsed B-acute lymphoblastic leukemia (B-ALL) generally occurs due to the emergence of subclones resistant to therapy, leading to poor outcome. Here, we describe novel genomic alterations responsible for therapeutic resistance at a subtype level in a clinical trial (AALL1331) which randomized patients to blinatumomab and chemotherapy versus chemotherapy alone. We performed whole-genome and transcriptome sequencing on 288 patients (183 diagnosis\/first relapse\/germline trios and 105 additional patients with first-relapse samples) and analyzed 41 second-relapse samples. For ETV6::RUNX1, we showed that cases with gain of the fusion allele or with fusion transcript involving exon 5 of ETV6 and exon 4 of RUNX1 (E5-E4) had a higher risk of first relapse than cases with E5-E3. For the hyperdiploid subtype, we demonstrated that low modal chromosomal numbers (51-52) were more prone to first relapse than those with \u226553 chromosomes, with an additive effect of CREBBP mutations. We showed enrichment of IKZF1 alterations in the Philadelphia-like subtype and that NSD2 E1099K was commonly associated with relapse in TCF3::PBX1. Together, these new features accounted for 30% (n=55) of first relapses. Intriguingly, ~3% of relapses are related to secondary B-ALL or germline predisposition. We also compared genomic alterations at diagnosis and first relapse in relation to second relapse status in randomized patients, with TCF3::PBX1\/NT5C2 linked to worse outcomes regardless of randomized arm. Together, our findings provide novel insights into the genomics of relapsed childhood B-ALL as well as in the context of blinatumomab therapy. This trial was registered at www.clinicaltrials.gov as # NCT0201853.<\/jats:p>","DOI":"10.1182\/blood.2025032369","type":"journal-article","created":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T19:01:11Z","timestamp":1793646071000},"update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":0,"title":["Identifying novel genomic alterations in relapsed childhood B-ALL: a report from the Children's Oncology Group"],"prefix":"10.1182","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-8932-4405","authenticated-orcid":false,"given":"Yuan","family":"Feng","sequence":"first","affiliation":[{"name":"St. Jude Children's Research Hospital, Memphis, Tennessee, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanxia","family":"Li","sequence":"additional","affiliation":[{"name":"St. Jude Children's Research Hospital, Memphis, Tennessee, United 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