Abstract
Nucleoporin 98 rearrangements (NUP98r) are recurrent in myeloid neoplasms and are subtype-defining for acute myeloid leukemia (AML) in the World Health Organization Classification 5th edition (WHO5) and the International Consensus Classification (ICC). Identification of NUP98r is essential given the frequency of treatment resistance and possibility of sensitivity to targeted therapies. However, NUP98r is often cryptic on karyotype and has over 40 described partners. Therefore, it is underdiagnosed in the absence of dedicated testing that is not always routine practice, e.g., RNA-based next generation sequencing (NGS), NUP98 break-apart fluorescence in situ hybridization, or real-time-quantitative polymerase chain reaction for specific NUP98 fusions. Historically, AML with NUP98r has received the most attention in pediatric AML, where its incidence is highest, but has been increasingly characterized in adult AML. By contrast, the incidence and behavior of NUP98 fusions in myelodysplastic syndromes (MDS) is less understood and based predominantly on case reports. In this study, we describe our adult institutional experience with a clinically validated anchored multiplex PCR RNA-based targeted NGS assay, explore strategies for rational use of specific testing for NUP98r including a proof-of-principle based on WT1 and FLT3- ITD mutational status, and integrate our results with a review of the literature. In total, we identified 3 MDS and 15 AML patients with NUP98r as the genetic driver, including two novel fusion partners (FGF14 and LAMC3), thus highlighting the utility of NGS testing to detect NUP98 fusions. Recognition of NUP98r in myeloid neoplasms is crucial for accurate diagnosis and prognosis, with significant implications for therapy or enrollment in clinical trials.