Mechanistic insights and potential therapeutic approaches for NUP98-rearranged hematologic malignancies

Abstract

Nucleoporin 98 (NUP98) fusion oncoproteins are observed in a spectrum of hematologic malignancies, particularly pediatric leukemias with poor patient outcomes. Although wild-type full-length NUP98 is a member of the nuclear pore complex, the chromosomal translocations leading to NUP98 gene fusions involve the intrinsically disordered and N-terminal region of NUP98 with over 30 partner genes. Fusion partners include several genes bearing homeodomains or having known roles in transcriptional or epigenetic regulation. Based on data in both experimental models and patient samples, NUP98 fusion oncoprotein-driven leukemogenesis is mediated by changes in chromatin structure and gene expression. Multiple cofactors associate with NUP98 fusion oncoproteins to mediate transcriptional changes possibly via phase separation, in a manner likely dependent on the fusion partner. NUP98 gene fusions co-occur with a set of additional mutations, including FLT3-internal tandem duplication and other events contributing to increased proliferation. To improve the currently dire outcomes for patients with NUP98-rearranged malignancies, therapeutic strategies have been considered that target transcriptional and epigenetic machinery, cooperating alterations, and signaling or cell-cycle pathways. With the development of more faithful experimental systems and continued study, we anticipate great strides in our understanding of the molecular mechanisms and therapeutic vulnerabilities at play in NUP98-rearranged models. Taken together, these studies should lead to improved clinical outcomes for NUP98-rearranged leukemia.

Graphical abstract

Figure 1.

Stucture of wild-type NUP98 and NUP98 fusions. (A) Structure of wild-type NUP98. (B) Structure of NUP98 fusions, including relevant functional domains and malignancies reported for each partner gene. The longest fusion gene is shown along with alternate breakpoints. Arrows denote breakpoints, and asterisk (*) denotes fusion partners for which multiple isoforms have been identified. CMML, chronic myelomonocytic leukemia; HMG, high-mobility group; IQ, isoleucine glutamine; JMML, juvenile myelomonocytic leukemia; MYST, MOZ, Ybf2, Sas2, and TIP60; PHD, plant homeodomain; SET, Su(var)3-9, enhancer-of-zeste and trithorax.

Figure 2.

NUP98 regulates transcription and cell cycle progression through interactions with cofactors. (A) NUP98 fusion oncoproteins bind to various transcriptional cofactors (including XPO1, WDR-SET1-COMPASS, and/or KMT2A complexes) and remodel chromatin. This leads to expression of target genes, possibly through the formation-phase separatory transcription centers. (B) Wild-type NUP98 associates with the anaphase-promoting complex (APC/C), RAE1, and other cell-cycle proteins, contributing to regulation of the spindle-assembly checkpoint. (C) NUP98 fusion oncoproteins bind to components of the APC/C including CDC20, leading to the ubiquitination and premature degradation of securin. In turn, activation of separation causes premature spindle-assembly checkpoint. Ac, acetyl; Me, methyl; MOF, males absent on the first; NSL, nonspecific lethal; P, phospho; Ub, ubiquitin.

Figure 3.

Co-altered genes and potential therapeutic approaches in NUP98-rearranged hematologic malignancies. (A) NUP98 fusion confers self-renewal and loss of differentiation. (B) Co-occurring alterations, including FLT3-ITD mutation, RAS mutation, and/or WT1 mutation may lead to a proliferative advantage and to hematologic malignancy. (C) Potential strategies for therapeutic targeting of hematologic malignancies with NUP98 gene fusions.