NUP98 rearrangements (NUP98r) in Acute Myeloid Leukemia (AML): A genomic landscape study

Abstract Background: Nucleoporin 98 rearrangements (NUP98r) occur in a wide range of hematologic malignancies including AML and have been shown to inhibit differentiation of hematopoietic precursors and to increase self-renewal of hematopoietic progenitor cells, providing a potential mechanism for malignant transformation. NUP98r is associated with adverse prognosis, especially in children. In this study we aimed to better understand genomic alterations (GA) with NUP98r in AML. Methods: 4,040 cases of AML underwent comprehensive genomic profiling using the Foundation One Heme combined hybrid capture-based DNA and RNA sequencing assay. All classes of GA were evaluated. Results: 47 (1.2%) AML cases featured NUP98r. The median age of the NUP98rAML cases was 19 years compared with 60 years for the NUP98 wild type cases (p=.039) with more than 40% of patients younger than 18 years. The male vs female sex distribution was similar and near 50/50 in both groups. The NUP98r AML cases were more frequently of admixed American (AMR) ancestry (29.8% vs 15.3%; NS) and less frequently of European (EUR) ancestry (57.4% vs 68.7%; NS). Individual GA more frequently identified in NUP98r cases included WT1 (25.5% vs 9.8%; p=.014), BRAF (6.4% vs 0.9%; p=.057); FLT3 (27.7% vs 20.9%; NS), IDH1 (10.6% vs 7.0%; NS), JAK2 (8.5% vs 3.8%; NS), KRAS (14.9% vs 9.1%; NS), NRAS (21.3% vs 17.4%; NS). GA more frequent in the NUP98 wild type AML cases included BCOR (2.1% vs 6.4%; NS), DNMT3A (4.3% vs 16.4%; NS), KMT2A (12.9% vs 2.1%; NS), NPM1 (4.3% vs 15.3%; NS) and RUNX1 (12.8% vs 19.5%; NS). Conclusions: NUP98r are rarely detected in AML, are more frequent in pediatrics and young patients (median age 19 years, 40% less than age of 18 years) but distributed in all age groups, found equally among sexes and associated with a unique genomic landscape that features both increased frequencies of some anti-AML targets such as FLT3 and IDH1 and decreased frequencies of others like KMT2A and NPM1. WT1 was more commonly seen in NUP98r, combination of both mutations with or without FLT3 has been shown to correlate with poor outcomes in pediatrics AML.