NUP98 Rearrangements in AML: Molecular Mechanisms and Clinical Implications

Abstract

NUP98 fusions constitute a small subgroup of AML patients and remain a high-risk AML subtype. There are approximately 30 types of NUP98 fusions identified in AML patients. These patients show resistance to currently available therapies and poor clinical outcomes. NUP98 fusions with different fusion partners have oncogenic transformation potential. This review describes how the NUP98 gene acquires oncogenic properties after rearrangement with multiple partners. In the mechanistic part, the formation of nuclear bodies and dysregulation of the HoxA/Meis1 pathway are highlighted. This review also discusses mutational signatures among NUP98 fusions and their significance in leukemogenesis. It also discusses the clinical implications of NUP98 fusions and their associated mutations in AML patients. Furthermore, it highlights therapeutic vulnerabilities in these leukemias that can be exploited as therapeutic strategies. Lastly, this review discusses the gaps in our knowledge regarding NUP98 fusions in AML, as well as future research opportunities.

Evaluation of Acute Myeloid Leukemia Genomes using Genomic Proximity Mapping

“…3C). While standard-of-care cytogenetics identified both KMT2A and NUP214 fusions, only CytoTerra identified the NUP98 fusion, a variant associated with poor outcomes(8). In this case, CytoTerra offers benefit in identifying variants of import over existing standard methods.…”

“…These variants included a NUP98::KDM5A fusion created by a t(11;12)(p15.4;p13.33), a variant associated with poor prognosis and chemoresistance (Fig. 3D) (8) . This rearrangement was not previously detected in the cytogenetics report for this patient.…”

Novel Therapeutic Targets in Acute Myeloid Leukemia (AML)

“…NUP98 fusions typically portend poor prognosis and may be associated with chemotherapy resistance [ 67 , 68 ]. Like MLL fusion and NPM1 mutations, NUP98 fusion proteins bind to chromatin near HOX genes resulting in their overexpression through a number of different mechanisms, including altered DNA methylation and acetylation [ 69 ]. The binding of NUP98 fusion genes to chromatin is dependent on both MLL and Menin, and in preclinical studies, leukemic cells harboring NUP98 fusions were shown to respond to Menin inhibition [ 70 ].…”