# Defining the genetic mechanisms of ETS1 dependency in Notch-activated T Cell Acute Lymphoblastic Leukemia (T-ALL)

> **NIH NIH F30** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $49,490

## Abstract

PROJECT SUMMARY
Over 60% of T cell acute lymphoblastic leukemias (T-ALLs) harbor mutations in the NOTCH1 signaling pathway,
making Notch activation the most common oncogenic pathway in T-ALL. However, pan-Notch inhibitors are
associated with dose-limiting toxicities, primarily gastrointestinal. We previously showed that the transcription
factor ETS1 is essential for Notch-activated T-ALL survival. ETS1 inhibition impairs T-ALL survival and
downregulates major oncogenic Notch target genes. Further, ETS1 deletion has limited toxicities in murine
models. These findings suggest targeting ETS1 might have strong anti-leukemic effects with more favorable
toxicity profile than Notch inhibitors. While ETS1 and NOTCH1 activate many overlapping pathways, the cis-
regulatory elements downstream of ETS1 are less well defined and may play a more essential role than NOTCH1
for activation of some T-ALL enhancers. I identified one such enhancer in which ETS1 may play a more essential
role than NOTCH1. Here, ETS1 is required to activate expression of MYB, a critical T-ALL oncogene (tentatively
named “E-Me” for ETS1-dependent MYB Enhancer). My preliminary data shows that ETS1 is required for E-Me
activation and MYB expression, and E-Me repression in human T-ALL cell lines inhibits MYB expression and
cell survival. Based on these preliminary studies, I hypothesize that ETS1 drives T-ALL survival by activating
the E-Me and other essential regulatory elements for T-ALL oncogenes. I will investigate this hypothesis through
two aims. In my first aim, I will determine the consequences of E-Me blockade in Notch-activated T-ALL survival
in vivo using two murine models. In my second aim, I will further define the cis-regulatory elements and
oncogenes downstream of ETS1 in T-ALL. The enhancers and transcription factor dependencies that regulate
oncogene expression in T-ALL arecurrently poorly understood, raising barriers to targeted therapeutic
strategies. My proposal will help close this gap in knowledge. Finally, the overall impact of this project will be to
define the role of ETS1 as a driver of essential T-ALL oncogenic pathways and enable the discovery of other
essential transcription factors in T-ALL.

## Key facts

- **NIH application ID:** 10995385
- **Project number:** 1F30CA288021-01A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Karena Hsijan Lin
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $49,490
- **Award type:** 1
- **Project period:** 2024-08-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10995385

## Citation

> US National Institutes of Health, RePORTER application 10995385, Defining the genetic mechanisms of ETS1 dependency in Notch-activated T Cell Acute Lymphoblastic Leukemia (T-ALL) (1F30CA288021-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10995385. Licensed CC0.

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