# Experimental and preclinical modeling of NUP98-rearranged acute leukemia

> **NIH NIH U54** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2020 · $25,642

## Abstract

Project 3/Summary 
NUP98 fusion oncogenes (e.g., NUP98-HOXA9, -KDM5A, and -NSD1) are associated with several 
hematological malignancies, including pediatric acute myeloid leukemia (AML), characterized by dismal 
treatment outcomes. The N-terminal FG-repeat domain that is common to all NUP98 fusion oncogenes 
(termed NUP98-N) is known to be intrinsically disordered and, by itself, to undergo phase separation to form 
gel-like bodies in vitro and large, spherical puncta in the nuclei of cells. However, these large puncta are not 
associated with hematopoietic cell transformation and leukemogenesis. Importantly, NUP98 fusion 
oncoproteins (FOs)—in which NUP98-N is fused to a variety of different C-terminal chromatin targeting 
domains—form many chromatin-associated, sub-micron-sized puncta that are associated with aberrant gene 
transcription, hematopoietic cell transformation and leukemogenesis. Recently, Young, et al., Tjian, et al., and 
Rivera, et al., demonstrated that critical transcriptional regulators, i) exhibit disordered regions that undergo 
phase separation in vitro and ii) are found within small, liquid-like puncta in cells that are proposed to form 
through phase separation. These dynamic puncta are proposed to drive co-localization of distal chromatin sites 
and organize the transcriptional machinery for coordinated expression of multiple genes. In the proposed 
studies, we will test the hypothesis that phase separation is a unifying mechanism that drives the formation of 
aberrant transcription centers by NUP98 FOs at chromatin sites targeted by their various C-terminal fused 
domains. These aberrant transcription centers, we propose, recruit components of the transcriptional 
machinery to activate expression of HOX and other genes and transform hematopoietic cells. 
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## Key facts

- **NIH application ID:** 10230529
- **Project number:** 3U54CA243124-01S2
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** RICHARD W KRIWACKI
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $25,642
- **Award type:** 3
- **Project period:** 2019-09-19 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10230529

## Citation

> US National Institutes of Health, RePORTER application 10230529, Experimental and preclinical modeling of NUP98-rearranged acute leukemia (3U54CA243124-01S2). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10230529. Licensed CC0.

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