The Silent Revolution of the Genome: The Role of Optical Genome Mapping in Acute Lymphoblastic Leukemia

Background: Acute lymphoblastic leukemia (ALL) is a genetically heterogeneous malignancy driven by structural variants (SVs) that impact diagnosis, prognosis, and treatment. Traditional methods such as karyotyping, FISH, and PCR often fail to detect cryptic or complex rearrangements, which are critical for accurate risk stratification. Methods: Optical Genome Mapping (OGM) is a technology that directly analyzes ultra-high-molecular-weight DNA, enabling the identification of balanced and unbalanced SVs, copy number variations (CNVs), and gene fusions with high resolution. This review compares the advantages and limitations of OGM versus standard techniques in ALL. Results: OGM improves ALL diagnosis by detecting clinically relevant alterations such as IKZF1 deletions, cryptic KMT2A rearrangements, and kinase fusions, especially in cases with normal or uninformative karyotypes. It reduces artifacts by eliminating cell culture and shortens reporting times. OGM resolves complex events like intrachromosomal amplifications and chromothripsis, enhancing classification and therapy decisions. Limitations include reduced sensitivity in repetitive regions, challenges in detecting Robertsonian translocations, difficulties with complex ploidies, and lower sensitivity for low-frequency subclones. Conclusions: Integrating OGM with next-generation sequencing (NGS) allows comprehensive genomic profiling, improving diagnosis, prognosis, and personalized treatment in ALL. Future advancements promise to further enhance the clinical utility of OGM.