NUP98 oncofusions in myeloid malignancies: An update on molecular mechanisms and therapeutic opportunities

Abstract

Acute myeloid leukemia (AML) is an aggressive hematological malignancy with a heterogeneous molecular landscape. In the pediatric context, the NUP98 gene is a frequent target of chromosomal rearrangements that are linked to poor prognosis and unfavorable treatment outcomes in different AML subtypes. The translocations fuse NUP98 to a diverse array of partner genes, resulting in fusion proteins with novel functions. NUP98 fusion oncoproteins induce aberrant biomolecular condensation, abnormal gene expression programs, and re-wired protein interactions which ultimately cause alterations in the cell cycle and changes in cellular structures, all of which contribute to leukemia development. The extent of these effects is steered by the functional domains of the fusion partners and the influence of concomitant somatic mutations. In this review, we discuss the complex characteristics of NUP98 fusion proteins and potential novel therapeutic approaches for NUP98 fusion-driven AML.

Figure 1

Schematic representation of NUP98 expression and structure in cells. (A) The expression involves alternative splicing and autoproteolytic cleavage, leading to the production of mature NUP98 and NUP96 proteins, as well as an 8 kD fragment. (B) The structure of the wild‐type NUP98 protein and position of NUP98 fusion breakpoints in leukemia. Arrows indicate exon numbers. GBD, Gle2‐binding domain; NLS, nuclear localization signal.

Figure 2

Graphical representation of wild type NUP98 and its fusion partner structures, which involve functional domains for each fusion partner. BAH, bromo‐adjacent homology; DBD, DNA binding domain; GBD, Gle2‐binding domain; HMG, high mobility group; LBD, ligand‐binding domain; NLS, nuclear localization signal; OM‐LZ, octapeptide motif‐leucine‐zipper; PWWP, Pro‐Trp‐Trp‐Pro; Q‐rich, glutamine‐rich; RNB, RNA‐binding domain. Functional domains for VRK1, LOC348801 (LNP1), FN1, and ANKRD28 have not been identified so far.

Figure 3

Schematic illustration of the NUP98 protein in healthy cells and interactions of NUP98 fusion proteins in AML cells. The mature wild‐type NUP98 protein is predominantly located in both the nucleus and cytoplasmic regions of the NPC, as well as in the nucleoplasm. The NUP98 fusion proteins are predominantly observed within nuclear punctate structures, known as biomolecular condensates, distributed throughout the nucleoplasm. Within these condensates, NUP98 fusions form their distinct protein interactome, where the N‐terminus FG repeats engage with various regulatory proteins. Specifically, the FG repeats interact with MLL, WSC, CBP/P300, and ASH1L protein complexes, all of which play roles in epigenetic regulation. Simultaneously, functional domains such as PHD and SET in fusion partners like NSD1 collaborate with this regulatory function or engage with chromatin. Figure Made in BioRender.com.

Figure 4

Graphical depiction of treatment opportunities for NUP98‐r AML.