# Dissecting the role of clonal evolution in NPM1-mutant AML

> **NIH NIH R00** · CINCINNATI CHILDRENS HOSP MED CTR · 2024 · $170,611

## Abstract

Project Summary/Abstract
Candidate: I am a postdoctoral fellow in the lab of Dr. Ross Levine in the Human Oncology & Pathogenesis
Program at Memorial Sloan Kettering Cancer Center (MSKCC). My PhD studies allowed me to hone the technical
and experimental skills required for interrogating clinically tractable molecular dependencies in cancer cells. My
current research focuses on the generation of models of acute myeloid leukemia (AML) evolution to be used in
the discovery of novel molecular dependencies and potential therapeutic targets. To that end, I have broadened
my capabilities with CRISPR editing to generate an inducible AML model that allows for temporal control of
mutagenesis and optimized a single cell DNA sequencing technique to evaluate the clonal framework of AML.
My proposed research will build upon these initial studies to develop a new suite of sequential mutagenesis
models of AML. These models developed in the K99 phase of this grant will serve as tools for the discovery of
essential proteins/pathways for leukemic cells. My long-term career goal is to lead an independent research
group focused on the identification and characterization of molecular dependencies of AML using precise models
of disease evolution through sequential mutagenesis. To accomplish these goals, I have outlined a career plan
that will 1) expand of my technical skills and scientific capacity, 2) improve my scientific communications with
the field, 3) advance my supervisory and leadership abilities, 4) develop and foster collaborative relationships
and 5) prepare me for the transition to independence.
Project: Molecular profiling studies of AML patients infer a progressive acquisition of mutations that drives
leukemogenesis, but are unable to delineate the dominant clonal framework leading to disease or identify the
precise mutational order for certain genes, such as NPM1. Current models of AML are unable to truly recapitulate
the step-wise mutagenesis observed in patients. Our single cell sequencing studies have further resolved the
clonal structure of AML at single cell resolution and with these studies, I aim to generate new models that
accurately depict the sequential mutagenesis of AML evolution. The specific aims are: 1) examine mechanisms
of co-mutational clonal dominance and mutation order in AML patients using single cell profiling, 2) determine
the impact of mutational acquisition on disease development and progression of NPM1-mutant AML, and 3)
elucidate molecular dependencies of disease derived from mutant NPM1 and co-occurring mutations.
Environment: The Levine lab is part of the MSKCC Molecular Cancer Medicine Service, Human Oncology &
Pathogenesis Program (HOPP), for which Dr. Levine is Chief. The Levine lab is a core member of the Center for
Hematologic Malignancies and the Center for Epigenetics Research, directed by Dr. Abdel-Wahab and Dr.
Kristian Helin, respectively. These affiliations at MSKCC, a state-of-the-art institution, provide a rich s...

## Key facts

- **NIH application ID:** 10893531
- **Project number:** 5R00CA252005-05
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Linde A Miles
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $170,611
- **Award type:** 5
- **Project period:** 2022-08-15 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10893531

## Citation

> US National Institutes of Health, RePORTER application 10893531, Dissecting the role of clonal evolution in NPM1-mutant AML (5R00CA252005-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10893531. Licensed CC0.

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