# Project 3 - Genomics of Secondary AML Progression.

> **NIH NIH P01** · WASHINGTON UNIVERSITY · 2020 · $442,088

## Abstract

Project 3: Genomics of secondary AML progression. The long-term goal of this project is to define the
mechanisms underlying subclone expansion during progression from myelodysplastic syndromes
(MDS) to secondary AML (sAML). Approximately 30% of patients with MDS, the most common adult myeloid
malignancy in the US, progress to a rapidly fatal secondary AML. We have shown that progression from MDS
to sAML is characterized by persistence of founding clone mutations, and expansion of one or more subclones.
Preliminary data from our group and others suggest that an acquired mutation in a signaling gene (e.g., NRAS)
or a myeloid transcription factor (e.g., RUNX1) may contribute to subclone and blast expansion in up to 50% of
MDS patients. What drives subclone expansion in the remaining 50% of patients is not yet clear. We
hypothesize that alternative genetic (i.e., non-coding or structural variants) or epigenetic alterations may also
contribute to progression. We will identify acquired alterations that drive subclone expansion in this project. In
Specific Aim 1, we will define the genomes and transcriptomes of rising subclones during progression
from MDS to sAML. We will perform enhanced whole genome sequencing on sample trios (skin, MDS, and
sAML bone marrow) to comprehensively define the clonal architecture of samples, including rising subclones
during progression. In parallel, we will perform single-cell RNA-sequencing (scRNA-seq) on MDS/sAML paired
samples to identify the expression signatures of subclones that evolve to cause sAML. By sequencing samples
with and without known subclonal driver gene mutations, we will test whether all rising subclones have
dysregulated expression of genes or pathways that control normal myeloid maturation. These studies will be
further informed by the data collected on de novo and TP53 mutated AML samples in projects 1, 2, and 4.
Collectively, these studies should define drivers of subclonal expansion that could potentially be targeted to
prevent sAML progression. In Specific Aim 2, we will functionally validate mutations that contribute to
subclone expansion during progression from MDS to sAML. The genes that cooperate with founding clone
mutations to drive subclone expansion are not always known. We hypothesize that common MDS-initiating
mutations in epigenetic modifier and spliceosome genes may “prime” a hematopoietic stem/progenitor cell
(HSPC), and make it more susceptible to progression by cooperating mutations; this in turn suggests that the
order of mutation acquisition may be important for sAML pathogenesis. We will test the importance of subclone
mutations by introducing them into primary mouse HSPCs that harbor a founding clone mutation using viral
over-expression, or CRISPR/Cas9 technology for loss-of-function and monitor self-renewal, proliferation, and
clonal expansion in recipient mice. We predict that only specific combinations of mutations--acquired in the
correct order--will cooperate to induce clo...

## Key facts

- **NIH application ID:** 9902353
- **Project number:** 5P01CA101937-16
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Matthew J Walter
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $442,088
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9902353

## Citation

> US National Institutes of Health, RePORTER application 9902353, Project 3 - Genomics of Secondary AML Progression. (5P01CA101937-16). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9902353. Licensed CC0.

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