# Project 2

> **NIH NIH U54** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2020 · $25,643

## Abstract

Our long-term goal is to elucidate molecular mechanisms of aberrant gene control in cancer and
develop innovative treatment strategies to improve the survival of children with refractory cancers
such as AML. The objective of this project, which is the next logical step towards this goal as part of
our collaborative U54 consortium, is to define and therapeutically target the oncogenic gene
expression control activity of NUP98 fusion protein complex in AML. Our central hypothesis is that
NUP98 fusion proteins generate an oncogenic chromatin remodeling protein complex that induces
leukemogenic gene expression, conferring aberrant leukemia cell growth and survival, and that its
molecular mechanisms and therapeutic targets can be defined using an innovative integration of
functional genomics and proteomics. This hypothesis is based on two essential preliminary studies
that the Armstrong and Kentsis labs have recently completed (3, 6), providing the impetus for this
project: 1) Discovery of the essential functional interaction between NUP98 fusion proteins and the
MLL1 and NSL chromatin remodeling complexes in AML; and 2) development of strategies to define
the architecture and therapeutic disassembly of cellular protein complexes. However, the precise
mechanisms linking NUP98 fusion protein complex assembly and leukemogenic chromatin functions
are not defined, constituting an important gap in knowledge that is required for the development of a
rational therapeutic strategy to treat fusion oncoprotein-activated AML. Aim 1 will elucidate the
mechanisms of leukemogenic chromatin remodeling using inducible degradation of NUP98-fusion
proteins. In Aim 2, we will define the domains and interfaces involved in aberrant assembly of
NUP98-fusion chromatin remodeling complexes using in situ cross-linking mass spectrometry and
CRISPR domain scanning. And lastly, we will determine the anti-leukemia efficacy of targeted
epigenetic and protein interaction therapies using preclinical mouse models. Successful completion of
this proposal is expected to yield molecular mechanisms and effective therapies of NUP98 fusion
oncoprotein and gene control in AML, thus providing essential insights into a fundamental problem
that remains poorly understood. This research will have broad significance because fusion
oncoproteins and oncogenic gene expression contribute to the majority of human cancers. Finally, the
complementary interactions with other projects in this U54 consortium and development of effective
molecular therapies targeting NUP98 fusion proteins in AML would constitute a transformative
advance in the clinical care of patients with this disease, whose cure rates remain wholly inadequate
with current therapy.

## Key facts

- **NIH application ID:** 10230528
- **Project number:** 3U54CA243124-01S2
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** Charles G Mullighan
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $25,643
- **Award type:** 3
- **Project period:** 2019-09-19 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10230528

## Citation

> US National Institutes of Health, RePORTER application 10230528, Project 2 (3U54CA243124-01S2). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10230528. Licensed CC0.

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