# Dissecting the roles of Runx3 and Mll1 in dysfunctional T cell responses to tumors

> **NIH NIH F31** · SCRIPPS FLORIDA · 2020 · $32,520

## Abstract

Project Summary/Abstract:
CD8+ T cells differentiate into cytotoxic T lymphocytes (CTLs), to directly engage malignant cells and cause their
lysis via exocytosis of cytotoxic granules. However, the regulation underlying these responses to tumors is ill-
defined and generally unsuccessful compared responses to acute viral infections. In addition, studies have
shown that while inhibitory signal blockade can restore some T cell function, it does not lead to global epigenetic
reprogramming of dysfunctional cells. Nevertheless, basic studies to clarify the factors and mechanisms that
control chromatin structure and transcription in CD8 T cells reacting to tumors and viral infection are likely to
identify how this can be achieved.
To address these issues, I am interested in defining how transcription factor Runx3 and chromatin regulator Mll1
work separately and together to effect genome wide transcript expression, chromatin accessibility, and inhibitory
receptor expression in CTLs infiltrating triple negative breast cancers. I provide evidence that both Runx3 and
Mll1 expression levels can manipulate PD-1 expression and that Mll1 expression is linked to Runx3. I
hypothesize that by studying how these two genes work independently and in a coordinated fashion I can define
a network of gene regulation and chromatin accessibility that programs PD-1 expression, and more broadly,
understand more about the genetic architecture of CTLs infiltrating non-lymphoid tissues. To do, I propose two
specific aims: Elucidate how Runx3 programs CD8+ T cell differentiation during anti-tumor responses &
Understand the role of Mll1 in determining CTL function in tumor microenvironments.
Both aims will utilize a model of murine triple negative breast cancer, E0771, tagged with lymphocytic
choriomeningitis virus antigen GP33 to allow for antigen specific tumor targeting in proposed experiments. In
Aim 1, I will identify the key genetic and epigenetic landscapes through which Runx3 acts and how this relates
to PD-1 function. Previous research has shown that Runx3 is necessary to generate non-lymphoid and tumor
residency and also programs the expression of inhibitory genes such as PD-1. By studying these features, I can
identify what pathways this apical transcription factor works through and how this effects PD-1 expression. In
Aim 2, I will be investigating the role Mll1 plays in similar pathways. Mll1 was identified through an in vitro RNAi
screen for chromatin regulators that modulated co-inhibitory genes. From this screen Mll1, and genes that make
up the MLL1/2 complex, are heavily implicated in inhibiting PD-1 expression. By looking at how Mll1 functions in
CTLs within the TME and what changes it promotes both in accessibility and methylation, I can understand how
these changes in chromatin directs CTL fates in tumors. Combined with understanding Runx3 and the
relationship between the genes, this will provide detailed evidence into the fundamental genetic architecture
und...

## Key facts

- **NIH application ID:** 9904112
- **Project number:** 5F31CA232380-02
- **Recipient organization:** SCRIPPS FLORIDA
- **Principal Investigator:** Adam Joshua Getzler
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $32,520
- **Award type:** 5
- **Project period:** 2019-04-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9904112

## Citation

> US National Institutes of Health, RePORTER application 9904112, Dissecting the roles of Runx3 and Mll1 in dysfunctional T cell responses to tumors (5F31CA232380-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9904112. Licensed CC0.

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