# Investigating Type I Interferon response and differentiation in FLT3-inhibitor persistent acute myeloid leukemia

> **NIH CA R37** · UNIVERSITY OF PENNSYLVANIA · 2026 · $434,969

## Abstract

PROJECT SUMMARY
Acute myeloid leukemia (AML) is a genetically and cellularly heterogenous disease characterized by the
expansion of hematopoietic cells across a range of cell states from stem-like cells to differentiated myeloid cells.
The most mutated genes in AML are DNMT3A, NPM1 and the receptor tyrosine kinase FLT3. Despite early
clinical responses, most patients relapse, and FLT3-mutant clones are not always eradicated. Our lab has
developed genetically engineered mouse models of acute myeloid leukemia that are capable of activating
mutations in Flt3 with Dre-recombinase, and then genetically reverting them with Cre-recombinase. We have
used these models to benchmark Flt3 oncogene-addiction against best-in-class small molecule kinase inhibitors
of FLT3, observing difference in disease remission and relapse. These studies have refined our interest on
identifying which cells along the hematopoietic hierarchy are capable of driving relapse and which molecular
pathways underlie their survival following chemical/genetic inhibition of FLT3. The major goal of this proposal is
to understand the cellular mechanisms that maintain FLT3-mutant clone persistence during targeted therapy.
Our preliminary data indicate that Flt3-inhibtion results in a profound differentiation response and induction of
Type I Interferon signaling. We will complete integrative studies with human specimen and our innovative multi-
recombinase mouse models of leukemia to derive clinically meaningful insights from mechanistic observations
in model systems. In aim 1 we will determine which cells are capable of propagating leukemic disease and
resolve cellular reservoirs of leukemic stem cell activity. We will perform these studies using genetically
engineered mouse models, serial transplantation of purified cell populations, and functional cell ablation studies.
We hypothesize that FLT3-inhibtion induced differentiation generates mature cells that are capable of reacquiring
stem-like properties and 

## Key facts

- **NIH application ID:** 11276142
- **Project number:** 1R37CA307677-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Robert Lyle Bowman
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** CA
- **Fiscal year:** 2026
- **Award amount:** $434,969
- **Award type:** 1
- **Project period:** 2026-05-01T00:00:00 → 2031-04-30T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11276142

## Citation

> US National Institutes of Health, RePORTER application 11276142, Investigating Type I Interferon response and differentiation in FLT3-inhibitor persistent acute myeloid leukemia (1R37CA307677-01). Retrieved via AI Analytics 2026-07-07 from https://api.ai-analytics.org/grant/nih/11276142. Licensed CC0.

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