# Genetically faithful modeling of NUP98 rearrangement and co-alterations in acute myeloid leukemia

> **NIH NIH F32** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2022 · $67,582

## 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 patient outcomes
(approximately 35% 5 year overall survival). NUP98 rearrangements lead to expression of oncogenic chimeric
gene fusions involving the 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 leukemia genomic sequencing studies, including those by my
laboratory, have shown that NUP98 fusions are commonly accompanied by recurring genetic events in distinct
subsets of AML, suggesting the importance of co-alterations in lineage-specific leukemogenesis. This research
proposal seeks to elucidate the effects of co-alterations in NUP98-rearranged AML, thus building on previous
studies with genetically faithful systems that could present undiscovered therapeutic vulnerabilities in this high-
risk leukemia subset. Aim 1 will evaluate the effects of co-altered genes in NUP98 FO-driven leukemogenesis.
I will use lentiviral overexpression and CRISPR/Cas9-based approaches to perform gene editing in
hematopoietic stem and progenitor cells (HSPCs) to introduce NUP98 FO and/or co-alteration, and I will study
the in vitro and in vivo consequences of these alterations using colony forming unit and bone marrow
transplantation assays, respectively. Immunophenotyping, pathology, and genomic characterization will be used
to determine the role of individual and combined genetic events on distinct disease states. Aim 2 will examine
the molecular mechanisms that occur at the transcriptional and epigenetic level when NUP98 FO and relevant
co-alterations are expressed alone or in concert. Using RNA sequencing, Cleavage Under Targets and Release
Using Nuclease (CUT&RUN), and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq),
I will integrate the gene expression profiles, DNA binding properties and histone modifications, and regions of
activate chromatin, respectively, that accompany expression of NUP98 FO and/or co-alteration. This multiomic
approach will provide a robust dataset for the investigation of the gene-regulatory effects of NUP98 fusions and
frequent co-alterations as well as for validation of their functional consequences. Together, these studies will
uncover lineage-specific and molecular impacts of cooperation between recurrent genetic events and NUP98
rearrangements in AML, revealing novel opportunities for therapeutic exploitation to impr...

## Key facts

- **NIH application ID:** 10443579
- **Project number:** 5F32CA261011-02
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** Nicole Michmerhuizen
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $67,582
- **Award type:** 5
- **Project period:** 2021-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10443579

## Citation

> US National Institutes of Health, RePORTER application 10443579, Genetically faithful modeling of NUP98 rearrangement and co-alterations in acute myeloid leukemia (5F32CA261011-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10443579. Licensed CC0.

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