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  • From Clonal Evolution to Relapse: Genomic and Epigenetic Drivers of Treatment Resistance in Pediatric B-Cell Acute Lymphoblastic Leukemia — A Systematic Review

  • Reyhaneh Ashjari Aghdam,1,*
    1. B.Sc. Graduate in Cell and Molecular Biology, Islamic Azad University, Tabriz Branch, Tabriz, Iran


  • Introduction: Pediatric B-cell acute lymphoblastic leukemia (B-ALL) is the most common childhood malignancy. Although risk-adapted therapeutic strategies have markedly improved survival outcomes, relapse remains a major challenge and a leading cause of treatment failure. Increasing evidence suggests that genomic alterations and epigenetic reprogramming contribute to clonal evolution, treatment resistance, minimal residual disease (MRD) persistence, and disease recurrence. This systematic review summarizes current evidence regarding the molecular mechanisms connecting genomic and epigenomic alterations with relapse development in pediatric B-ALL.
  • Methods: A PRISMA-guided systematic review was designed to identify relevant studies from PubMed/MEDLINE, Scopus, and Web of Science. Studies published from 2010 onward were prioritized, with inclusion of key earlier landmark studies when relevant. Eligible studies investigated pediatric B-ALL and evaluated genomic, transcriptomic, or epigenomic alterations associated with relapse, treatment resistance, or diagnosis–relapse evolution. Studies focusing on adult leukemia, non-B-ALL subtypes, case reports, or lacking molecular analyses were excluded. Data extraction focused on recurrent molecular alterations, clonal dynamics, epigenetic changes, and clinical implications, followed by qualitative synthesis of findings.
  • Results: Integrated genomic analyses indicate that relapse-associated clones frequently harbor alterations affecting lymphoid development, kinase signaling pathways, tumor suppressor mechanisms, and cellular drug response. Major molecular abnormalities associated with adverse outcomes include IKZF1 deletions, particularly IKZF1plus profiles, CRLF2 alterations, the BCR::ABL1-like molecular subtype, TP53 abnormalities, RAS pathway mutations, and CDKN2A/B deletions. Relapse-associated alterations involving NT5C2 and CREBBP further demonstrate therapy-driven clonal selection. Epigenetic dysregulation contributes to leukemia persistence through changes in DNA methylation, chromatin accessibility, enhancer activity, and transcriptional regulation. Clonal evolution studies demonstrate that relapse may emerge from rare pre-existing subclones present at diagnosis that undergo selection and expansion under therapeutic pressure. These evolutionary processes contribute to resistance, MRD persistence, and disease recurrence.
  • Conclusion: Relapse in pediatric B-ALL is driven by a complex interaction between genomic alterations, epigenetic reprogramming, and clonal evolution. Integrated molecular profiling and multi-omics approaches may improve relapse risk assessment and support personalized therapeutic strategies. Further studies combining genomic, epigenomic, and single-cell approaches are required to advance precision oncology and improve outcomes for high-risk pediatric B-ALL patients.
  • Keywords: Pediatric B-ALL; Clonal Evolution; Genomics; Relapse; Drug Resistance

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