Identifying novel genomic alterations in relapsed childhood B-ALL: a report from the Children's Oncology Group
Year: 2026
Type: article
Abstract: 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 ≥53 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.
Source: Blood
Authors: Yuan Feng, Hanxia Li, Heather L. Mulder, Ying Shao, Emily Michelle Plyler, Yanling Liu, Pandurang Kolekar, Samuel W Brady, Daniel Putnam, Tyler Jones, Andrea McBride, Alexis Eckert, Christian Deardorff, Monta Briviba, Quang Tran, Zhikai Liang, Li Fan, Scott Foy, Alexandra Stellwagen, Ti-Cheng Chang, Wenan Chen, Stanley B Pounds, Gang Wu, Xiang Chen, Charles G. Mullighan, Lingyun Ji, Laura Hogan, Teena Bhatla, Deepa Bhojwani, Karen R Rabin, Mary Shago, Andrew J. Carroll, John Easton, Jinghui Zhang, Stephen P Hunger, David T. Teachey, William L Carroll, Patrick A. Brown, Mignon L. Loh, Xiaotu Ma
Institutions: St. Jude Children's Research Hospital, Nationwide Children's Hospital, National Institute of Research and Innovation, University of Richmond, Mayo Clinic, University of Southern California, Stony Brook University Hospital, Stony Brook Children's Hospital, Newark Beth Israel Medical Center, Children's Hospital Los Angeles, University of California, San Francisco, Hospital for Sick Children, University of Alabama at Birmingham, Children's Hospital of Philadelphia, NYU Langone Health, New York University, Seattle Children's Hospital, University of Washington
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $5,500
Awards: G425884651, Children's Oncology Group Statistics and Data Center, COG NCTN Network Group Operations Center, G5368822766, Identifying Relapse Predictors and Therapeutic Vulnerabilities in Ph+ and Ph-like Acute Lymphoblastic Leukemia, Cancer Center Support Grant (CCSG), Tracking Therapy-Resistant Alterations in Childhood Acute Lymphoblastic Leukemia
OpenAlex ID: W7225102402