Novel NUP98::ASH1L Gene Fusion in Acute Myeloid Leukemia Detected by Optical Genome Mapping

SIMPLE SUMMARY: Structural genetic variants, such as gene fusions, are frequently detected in hematologic neoplasias. Over the past few decades, these structural variants have gained clinical impact via their guidance of disease classification and risk stratification. NUP98-rearrangements are recurrent in different hematologic neoplasias, fusing the gene NUP98 to a wide variety of partners. As they are often cytogenetically cryptic, other methodologies are required for the detection and identification of genetic fusion partners. Here, a previously unrecognized NUP98::ASH1L fusion was detected in a patient with acute myeloid leukemia with prior myelodysplastic/myeloproliferative neoplasia using a genome-wide approach through optical genome mapping. Using this technique, the clonal evolution of structural aberrations was detected during the early relapse after allogeneic stem cell transplantation. These findings give a putative explanation for the aggressive disease course and demonstrate the potential of this method for consecutive disease monitoring. ABSTRACT: Optical genome mapping (OGM) recently has demonstrated the potential to improve genetic diagnostics in acute myeloid leukemia (AML). In this study, OGM was utilized as a tool for the detection of genome-wide structural variants and disease monitoring. A previously unrecognized NUP98::ASH1L fusion was detected in an adult patient with secondary AML. OGM identified the fusion of NUP98 to Absent, Small, or Homeotic-Like Histone Lysine Methyltransferase (ASH1L) as result of a complex structural rearrangement between chromosomes 1 and 11. A pipeline for the measurement of rare structural variants (Rare Variant Pipeline, Bionano Genomics, San Diego, CA, USA) was used for detection. As NUP98 and other fusions are relevant for disease classification, this demonstrates the necessity for methods such as OGM for cytogenetic diagnostics in AML. Furthermore, other structural variants showed discordant variant allele frequencies at different time points over the course of the disease and treatment pressure, indicating clonal evolution. These results support OGM to be a valuable tool for primary diagnostics in AML as well as longitudinal testing for disease monitoring and deepening our understanding of genetically heterogenous diseases.