The NUP98 protein plays a fundamental role in various cellular activities. Understanding its normal operations is key to recognizing how its dysfunction can lead to adverse health conditions.
NUP98’s Role in the Cell
NUP98 is a component of the nuclear pore complex (NPC), a large structure embedded in the nuclear envelope that acts as a gateway between the nucleus and the cytoplasm. The NPC regulates the passage of molecules, allowing small ions and polypeptides to diffuse freely while actively transporting larger macromolecules like messenger RNA (mRNA) and proteins. NUP98 and NUP96 are involved in this bidirectional transport. NUP98 is localized to the nucleoplasmic side of the NPC, contributing to both nuclear import and export processes.
Beyond its role in physical transport, NUP98 also participates in regulating gene expression. It can dynamically associate with chromatin, the complex of DNA and proteins within the nucleus, and influence the activity of certain genes. This suggests that NUP98 helps connect RNA transcription, the process of creating RNA from DNA, with RNA export from the nucleus. Its presence within the nucleus, beyond the pore, indicates its involvement in cellular processes like mitotic progression.
How NUP98 Contributes to Disease
NUP98 can contribute to pathological conditions through genetic alterations, specifically chromosomal translocations. These translocations involve a segment of one chromosome breaking off and attaching to another, leading to the formation of abnormal NUP98 fusion proteins. The NUP98 gene fuses with many partner genes in such rearrangements. These fusion proteins retain a portion of NUP98 that can activate transcription.
The abnormal NUP98 fusion proteins disrupt normal cellular processes by altering gene regulation and RNA processing. Many NUP98 fusion partners encode homeodomain proteins, which are transcription factors. When fused with NUP98, these chimeric proteins act as aberrant transcription factors, leading to the dysregulation of gene expression. This disruption involves the upregulation of specific gene clusters, such as the HOXA cluster, which are involved in regulating hematopoietic stem and progenitor cell self-renewal. The resulting uncontrolled cell growth or differentiation contributes to the development of various diseases.
Diseases Linked to NUP98 Abnormalities
NUP98 abnormalities are implicated in various types of leukemia, particularly acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Chromosomal rearrangements involving the NUP98 gene are observed in a significant percentage of pediatric and adult AML cases. These NUP98 fusions are considered a high-risk subtype of AML and are associated with a poor prognosis.
In pediatric AML, the complete remission rate for patients with NUP98 rearrangements is significantly lower than in patients without these fusions. The three-year event-free survival rate for NUP98-positive patients is also lower. NUP98::NSD1 and NUP98::KDM5A are among the most prevalent fusion events in these conditions. The presence of NUP98 fusions indicates a distinct entity within leukemia with specific clinical and biological features, often presenting with symptoms like fatigue, weakness, fever, and easy bruising or bleeding.
Developing Treatments for NUP98-Related Conditions
Understanding the role of NUP98 and its fusion partners is guiding the development of novel therapies for NUP98-related diseases. Targeted drugs are emerging as promising options to improve treatment outcomes. For instance, cyclin-dependent kinase 6 (CDK6) has been identified as a direct target of NUP98-fusion proteins. Inhibitors of CDK4/6, such as Palbociclib, have shown anti-proliferative effects on AML cells driven by NUP98 fusions in laboratory settings.
Further research is exploring combination therapies to enhance effectiveness. Combining a drug that targets menin, a protein involved in regulating leukemic gene expression, with another that targets the acetyltransferases MOZ/KAT6A and HBO1/KAT7, which interact with NUP98 fusions, has shown promising results in mouse models. These ongoing efforts highlight the potential for personalized medicine approaches, where treatments are tailored based on the specific NUP98 fusion and its impact on cellular pathways.