# Aberrant STAT Function in CEBPA-mutant Acute Myeloid Leukemia

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2024 · $75,799

## Abstract

ABSTRACT
Acute Myeloid Leukemia (AML) is a hematologic malignancy characterized by the accumulation of immature
myeloblasts in the bone marrow and blood. Classically, AML is thought to arise due to a combination of signaling
mutations that increase proliferation and transcription factor mutations that impair differentiation. A prototypical
example of signaling activation in AML results from mutations in the growth factor receptor, Colony Stimulating
Factor 3 Receptor (CSF3R). Mutations in CSF3R, such as CSF3RT618I, cause constitutive activation of the
receptor in the absence of ligand and robust signaling through the JAK/STAT pathway. This causes activation
of downstream transcription factors—STAT3 and STAT5, to promote the proliferation of progenitor cells and their
differentiation down the myeloid lineage. In patients with AML, mutations in CSF3R are associated with high
rates of relapse and poor overall survival, but the advent of effective therapies for these patients has remained
elusive. CSF3R mutations alone are insufficient to cause AML and require a second mutation that impairs
myeloid differentiation. The most common co-occurring mutations are loss-of-function mutations in critical
myeloid transcription factors, such as CCAAT binding protein alpha (CEBPA). In AML, CEBPA mutations block
CSF3R-driven differentiation, leading to the accumulation of immature myeloid blasts. This differentiation arrest
is a fundamental feature of the aggressive phenotype associated with CSF3R-driven AML. The objective of this
project is to understand the mechanism by which CEBPA mutations impair CSF3R-driven differentiation. The
aims of this project are to (1) determine the effect of CEBPA mutations on localization of STAT3 to regulatory
elements of differentiation-associated genes and (2) to understand the effect of mutant CEBPA on cellular
signaling pathways. A novel mouse cell line model of myeloid differentiation with biallelic Cebpa mutations
analogous to those found in patients with AML will facilitate the successful completion of these aims. A
combination of transcription factor profiling, gene expression, chromatin architecture and phospho-proteomics
will be used to nominate mechanistic targets. Follow up studies will perturb these targets to determine their role
in mutant-CEBPA driven differentiation block. AML is a devastating disease with poor outcomes despite
chemotherapeutic treatments. Understanding how mutant CEBPA impairs differentiation will help create a
mechanistic foundation for the development of more efficacious therapies to treat patients this disease.

## Key facts

- **NIH application ID:** 10975585
- **Project number:** 3R01CA247943-04S1
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Julia E Maxson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $75,799
- **Award type:** 3
- **Project period:** 2021-02-05 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10975585

## Citation

> US National Institutes of Health, RePORTER application 10975585, Aberrant STAT Function in CEBPA-mutant Acute Myeloid Leukemia (3R01CA247943-04S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10975585. Licensed CC0.

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