# Dysregulation of Innate Lymphoid Immunity in Acute Myeloid Leukemia

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2021 · $514,434

## Abstract

PROJECT SUMMARY
Our proposal investigates a mechanism underlying innate immune dysfunction in acute myeloid leukemia (AML),
the leading cause of leukemia-related deaths in the U.S. The innate immune system naturally defends against
malignancy, however AML evades immunosurveillance to drive disease progression. Natural killer (NK) cells are
the primarily innate lymphoid cell (ILC) responsible for anti-tumor immune surveillance, and reduced NK cell
function both in de novo AML and in the post-transplant setting is correlated with poor outcomes. We have
recently discovered that AML patients carry a fundamental defect in NK cell development leading to specific
depletion of a sub-population of NK cells with critical roles in coordinating innate and adaptive immune
responses, as well as mature NK cell development and function.
We have shown that NK cells develop from a common innate lymphoid cell precursor (ILCP), which generates
a series of NK developmental intermediates (NKDIs) leading to mature, cytotoxic NK cells. ILCPs also give rise
to the other members of the ILC family, a diverse group of non-cytotoxic, cytokine-producing “helper” ILCs that
are known to be pro-tumorigenic. Our preliminary studies show that AML disrupts the NK lineage, shifting
production towards helper ILCs. As these populations all stem from the ILCP, this suggests AML is acting on
ILCPs to alter lineage fate specification. Lineage specification occurs through carefully controlled activities of
transcription factors that modify the epigenomic landscape generating stable cell type-specific gene expression
patterns. Our preliminary studies have uncovered an aberrant, helper ILC-like DNA methylation signature in
NKDIs isolated from AML patients and following leukemic cell co-culture. One key transcription factor is the aryl
hydrocarbon receptor (AHR), which we have found shifts the helper ILC/NK ratio in the presence of AHR ligands
ectopic produced by AML cells. We propose a strategy where the combination of AHR inhibition and
hypomethylating agents (HMAs) guides development to restore NK cell differentiation from the ILCP.
In this proposal, we will determine how AML drives this fate decision and promotes the generation of helper ILCs
by performing detailed epigenetic and functional analyses of ILCPs isolated from normal donors and AML
patients, including investigation in an immunocompetent murine AML model. We will investigate functional and
epigenetic poising of lineage fate including the role of AHR. Secondly, we will determine the relationship of the
NK cell defect in AML patients to epigenetic programming and disease progression, and directly test the impact
of HMAs on ILCP and NKDI development. We will also determine the preclinical efficacy of combining both HMA
and a novel AHR inhibitor to restore normal NK cell epigenetic programming and enhance NK cell generation to
improve outcomes in preclinical models of AML. Maintaining functionally mature NK cells and supporting
im...

## Key facts

- **NIH application ID:** 10299223
- **Project number:** 1R01CA255860-01A1
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Bethany Mundy-Bosse
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $514,434
- **Award type:** 1
- **Project period:** 2021-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10299223

## Citation

> US National Institutes of Health, RePORTER application 10299223, Dysregulation of Innate Lymphoid Immunity in Acute Myeloid Leukemia (1R01CA255860-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10299223. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*