# Epigenetics of Mutation-Order in Acute Myeloid Leukemia

> **NIH NIH K08** · OREGON HEALTH & SCIENCE UNIVERSITY · 2020 · $162,451

## Abstract

PROJECT SUMMARY
Acute myeloid leukemia (AML) develops as a result of the stepwise acquisition of mutations ultimately
resulting in malignant transformation. Mutations that alter the epigenome occur early in disease
development, while mutations that activate signaling pathways occur later. I have developed an
experimental system in which mutation order can be directly manipulated in vivo. Using this system, I
demonstrate that mutations in the transcription factor CCAAT enhancer binding protein alpha (CEBPA)
must occur prior to mutations in Colony Stimulating Factor 3 Receptor (CSF3R) in order for leukemia to
develop. In Aim 1, I will investigate whether the epigenetically similar core binding factor (CBF) AML also
demonstrates order dependence with co-occurring signaling mutations. I will also establish the
consequences of mutation order on the epigenetic landscape of developing hematopoietic progenitors.
In Aim 2, I will evaluate the role of lysine demethylase 1 as a driver of CSF3R/CEBPA mutant AML
through epigenetic profiling and loss of function studies. In Aim 3, I will identify novel therapeutic
approaches that reverse the epigenetic dysfunction seen in CEBPA/CBF AML and restore the
differentiation potential of AML blasts.
My goal is to become a successful independent investigator and a leader in the field of leukemia
genomics and targeted therapy. I will continue to conduct mentored research in the Laboratory of Dr.
Brian Druker, a pioneer in the field of targeted cancer therapy and Director of the Knight Cancer
Institute. I will undertake additional training in the area of cancer epigenetics and bioinformatic analysis
with the guidance of my mentorship committee members Dr. Lucia Carbone and Dr. Joshi Alumkal as
well as my and collaborator Dr. Hisham Mohammed. I will continue to see patients with hematologic
malignancy ½ day weekly in the outpatient setting with the remainder of my time dedicated to research.
Dr. Druker and my mentorship team will assist me in obtaining my first R01 grant and in navigating the
transition to running an independent research group.

## Key facts

- **NIH application ID:** 9871483
- **Project number:** 1K08CA245224-01
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Theodore Paul Braun
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $162,451
- **Award type:** 1
- **Project period:** 2020-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9871483

## Citation

> US National Institutes of Health, RePORTER application 9871483, Epigenetics of Mutation-Order in Acute Myeloid Leukemia (1K08CA245224-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9871483. Licensed CC0.

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