# Functional and Pharmacologic Investigation of the NUP98 Fusion Oncoprotein Interactome

> **NIH NIH K99** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2024 · $140,959

## Abstract

PROJECT SUMMARY
Chromosomal translocations involving Nucleoporin 98 (NUP98) are observed in approximately 5% of pediatric
acute myeloid leukemia (AML) and are associated with resistance to therapy and poor outcome, with
approximately 35% 5 year overall survival. NUP98 rearrangements lead to expression of oncogenic chimeric
gene fusions involving the intrinsically disordered, N-terminal region of NUP98 and the C-terminal region of one
of over 30 identified partner genes. The partner genes commonly have domains with key functional properties,
including homeodomain moieties (e.g. HOXA9) and roles in transcriptional regulation (e.g. NSD1, KDM5A). In
complex with other machinery needed for gene regulation, NUP98 fusion oncoproteins (FOs) bind to the
promoters of many developmental genes. This leads to changes in chromatin structure, increased expression of
target genes, and aberrant hematopoietic self-renewal. Recent studies, including my own, have shown that the
ability of NUP98 FOs to localize within the nucleus in membrane-less organelles, or “puncta” formed through
liquid-liquid phase separation (LLPS), is necessary for transformation and deregulated gene expression
phenotypes. Nevertheless, which proteins interact with NUP98 FOs in puncta and the importance of puncta
formation for effective therapeutic targeting of NUP98-rearranged cells is not known. This research proposal
seeks to identify the proteins found in NUP98 FO-associated puncta, uncover how puncta alter gene regulation,
and determine if puncta disruption correlates with effective treatment of NUP98-rearranged cells. Aim 1 will
examine the role of histone acetyltransferase (HAT) complex members, which my preliminary data identified as
key NUP98 FO interacting proteins, in NUP98::KDM5A FO-driven cell transformation. I will perform
CRISPR/Cas9 editing of HAT complex genes in hematopoietic stem and progenitor cells (HSPCs) from our
Nup98::Kdm5a mouse model and study the in vitro and in vivo consequences of these alterations. I will also
examine gene expression and chromatin remodeling in Nup98::Kdm5a HSPCs with and without HAT complex
disruption. Aim 2 will determine whether effective therapeutic targeting of NUP98 FOs leads to puncta disruption.
I will perform co-localization experiments for FO with proteins involved in nuclear transport and gene regulation.
I will then pharmacologically inhibit these interacting proteins using available small molecule inhibitors and
assess changes in puncta features and cell viability over time to determine if puncta disruption correlates with
drug efficacy. In Aim 3, I will identify interacting proteins that are vulnerabilities in NUP98-rearranged cells and
use pharmacologic inhibition of crucial interactors to identify how they are involved in cell transformation, gene
regulation, and LLPS. Together, these studies will identify critical interacting proteins in leukemias bearing
NUP98 gene fusions, examine how they contribute to leukemogenesis, and unc...

## Key facts

- **NIH application ID:** 10883772
- **Project number:** 5K99CA283256-02
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** Nicole Michmerhuizen
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $140,959
- **Award type:** 5
- **Project period:** 2023-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10883772

## Citation

> US National Institutes of Health, RePORTER application 10883772, Functional and Pharmacologic Investigation of the NUP98 Fusion Oncoprotein Interactome (5K99CA283256-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10883772. Licensed CC0.

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