Unveiling the Complexity of Rearrangements in Acute Myeloid Leukemias with Optical Genome Mapping.

rearrangements are major genetic entities in the classification of acute myeloid leukemias (AMLs), but their diverse and frequently cryptic nature makes their detection and characterization challenging. Karyotypic anomalies at the locus and/or abnormal Fluorescence in situ hybridization (FISH) results strongly indicate a fusion, but the identification of the translocation partner gene often requires further investigation. partial tandem duplications (PTDs), on the other hand, are undetectable by standard cytogenetics methods. We herein report the optical genome mapping (OGM) analysis of 38 AML samples: 12 cryptic/hard-to-characterize fusions, 20 -PTDs and 6 cases with no anomaly. In all the fusion cases, the rearrangement between 5' and the 3'partner gene was identified as a translocation t(v;11q23.3)(v;118479068), and the analysis of co-occurring variants elucidated the formation of the rearrangement. The variants detected in the -PTD cases were surprisingly diverse. Combined with RNAseq data, OGM analysis identified 9 distinct in-frame -PTD variants among the 20 cases analyzed. With the clinical development of menin inhibitors for the treatment of patients with -rearranged acute leukemias, the characterization of these rearrangements is of utmost importance. Our results suggest that OGM is a promising tool for accurate genetic diagnosis in this context.