Acute lymphoblastic leukaemia (ALL) is characterized by uncontrolled proliferation of lymphoid progenitor cells. Advances in genomic and epigenomic profiling have enabled the identification of over 40 molecular subtypes defined by distinct genetic drivers, transcriptional programmes and regulatory alterations. These insights have refined the classification, particularly of B cell precursor ALL (B-ALL) and are increasingly informing risk stratification, therapeutic decision-making and disease monitoring. By contrast, the classification of T cell ALL (T-ALL) has historically relied on immunophenotypic criteria, but recent large-scale genomic studies have uncovered biologically defined subtypes driven by diverse coding and noncoding alterations. Many genomic lesions represent clinically actionable vulnerabilities, including kinase-activating alterations that have enabled the use of targeted therapies. However, treatment resistance remains a major challenge, arising through clonal evolution, acquisition of secondary mutations and adaptive transcriptional and epigenetic reprogramming. In this Review, we highlight recent advances in understanding of the biological basis of ALL, with a focus on recently identified genetic alterations, gene expression patterns, alterations in three-dimensional genome architecture and epigenetic regulation that drive ALL initiation, progression and therapeutic response. Furthermore, we discuss how genetic heterogeneity contributes to clinical variability and how integrating molecular and biological insights can improve risk stratification and therapeutic outcomes.
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