Relapse in childhood B-cell precursor acute lymphoblastic leukemia: insights from transcriptomic signatures of diagnostic bone marrow.
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Survival rates exceeding 85% are now achieved for most children diagnosed with B-cell precursor acute lymphoblastic leukemia (BCP-ALL), the most common subtype of childhood ALL. Advances in the understanding of disease biology, the identification of robust prognostic factors, and the implementation of risk-adapted treatment protocols have enabled increasingly personalized therapeutic approaches. The integration of RNA sequencing into routine diagnostics has further refined subtype classification and facilitated the detection of cryptic rearrangements and pathogenic variants. Despite these improvements, a subset of patients still experience relapse-even those with favorable clinical and cytogenetic features as well as early clearance of residual disease. This overview underscores persistent gaps in current risk-stratification strategies; an important consideration, particularly for children assigned to low-risk groups who consequently receive reduced-intensity therapy. In this review, we synthesize current evidence on the diagnostic transcriptomic profiles in BCP-ALL that are associated with relapse, framing the discussion around five interconnected biological domains, namely cell death dysregulation and stress-adaptive survival; immune modulation and metabolic adaptation; developmental dysregulation and stemness; drug resistance; and post-transcriptional regulation. We focus specifically on transcriptomic signatures detectable at initial diagnosis, which reflect intrinsic leukemic cell states prior to therapeutic exposure, that may provide early indicators of relapse susceptibility. With the increasing availability of RNA-sequencing data across treatment centers, new opportunities are emerging to analyze these datasets beyond conventional subtype assignment. Comprehensive interrogation of transcriptomic profiles may help identify relapse-associated signatures that complement established clinical and genomic markers. As contemporary protocols continue to explore treatment de-intensification to minimize long-term toxicities, it is essential to ensure that patients classified as "low-risk" are accurately identified and do not harbor occult molecular features that predispose to relapse. This review provides a narrative overview of the transcriptomic determinants of relapse in BCP-ALL at diagnosis and highlights key knowledge gaps. By delineating the molecular pathways that may contribute to relapse, we aim to improve relapse prediction and provide a framework for future development of precise, personalized therapeutic strategies.