# Project 1 - Genomics of Intermediate-Risk AML Progression and Relapse.

> **NIH NIH P01** · WASHINGTON UNIVERSITY · 2022 · $433,281

## Abstract

Project Summary/Abstract
Project 1: Genomics of intermediate-risk AML progression and relapse. The long-term goal of this
project is to better understand the genetic and epigenetic events that contribute to the progression
and relapse of patients with intermediate-risk AML, and exploit them therapeutically. Intermediate-risk
AML (which is most commonly initiated by DNMT3A mutations) can have vastly different outcomes, for
reasons that are still not well understood. In this proposal, we will explore the genetic and epigenetic factors
that influence how a pre-leukemic, ancestral clone progresses to AML (i.e. “progression”), and then evolves to
recur after a remission (i.e. “relapse”). Virtually all AML samples are clonally heterogeneous at presentation,
generally containing one or more subclones derived from a founding clone (or other subclones). Subclones
often display different susceptibilities to therapies, and therapy-resistant subclones often evolve with new
mutations that are not recognized as drivers at relapse. To determine whether epigenetic factors may also be
relevant for subclonal evolution, we have performed pilot studies using single-cell RNA-sequencing (scRNA-
seq), and defined transcriptional evolution at relapse, and detected relapse-specific, differentially expressed
genes that were not detectable by bulk RNA-sequencing. In this proposal, we will exploit single cell methods to
better understand subclonal evolution at relapse, and evaluate the role of DNMT3A mutations for patterns of
gene expression at presentation and relapse. We will also determine whether initiating mutations in DNMT3A
are required only for creating the preleukemic “state”, or whether they are also relevant for maintaining fully
transformed AML cells. The studies of both aims may improve risk assessment and therapeutics for AML:
Specific Aim 1: We will define the events that contribute to clonal evolution and relapse in
intermediate-risk AML patients. We will perform enhanced whole genome sequencing (eWGS) and scRNA-
seq on matched presentation and relapse samples from intermediate-risk AML samples, which will allow us to
impute the expression signatures of subclones, how they progress at relapse, and identify genes and/or
pathways that are commonly dysregulated in dominant relapse subclones.
Specific Aim 2: We will define the role of DNMT3A mutations for AML initiation and maintenance. We
have generated Dnmt3a deficient mice with an inducible WT DNMT3A transgene (“Dnmt3a null-3A addback”
mice) that can accurately remethylate the genomes of transplanted bone marrow cells. We will generate similar
addback mice with a conditional Dnmt3aR878H mutation, define their DNA methylation phenotype, and
characterize their remethylation kinetics and accuracy with DNMT3A restoration. We will create a variety of
cooperating mutations in both models to cause AML, and then determine whether these AMLs can have their
growth and/or differentiation altered by restoring DNMT3A expr...

## Key facts

- **NIH application ID:** 10311208
- **Project number:** 5P01CA101937-18
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Timothy J. Ley
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $433,281
- **Award type:** 5
- **Project period:** 2003-09-19 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10311208

## Citation

> US National Institutes of Health, RePORTER application 10311208, Project 1 - Genomics of Intermediate-Risk AML Progression and Relapse. (5P01CA101937-18). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10311208. Licensed CC0.

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