# Stage-specific roles for Zmiz1 in Notch-dependent steps of early T-cell development

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $508,593

## Abstract

ABSTRACT
The discovery of NOTCH1 mutations in T-cell Acute Lymphoblastic Leukemia (T-ALL) patients raised hopes
for pan-Notch inhibitors to treat this cancer. Unfortunately, in clinical trials, these drugs were too toxic because
Notch has essential normal functions. Thus, the challenge is to selectively target Notch in T-ALL cells. Since
Notch activity requires cofactors at its enhancers to create favorable cell type-specific “chromatin contexts”, we
envision that targeting these cofactors might avoid the intolerable effects of pan-Notch inhibition. Thus, our
long-term goal is to understand the T-cell biology of Notch cofactors. For example, we discovered that the
PIAS-like coactivator Zmiz1 is a direct cofactor of Notch1 that selectively promotes Notch activity at the T-cell
specific Myc enhancer. Zmiz1 withdrawal or disrupting the Zmiz1-Notch1 interaction impaired Myc-dependent
proliferation of pre-T cells and leukemic blasts. Importantly, ubiquitous inactivation of Zmiz1 did not have major
effects on non-T cell tissues, suggesting more T-cell specific effects than Notch inhibition. For this proposal, we
observed that the expression of Zmiz1 in pre-T cells dramatically increases from steady state levels during
thymic regeneration. Accordingly, the Zmiz1-deficient pre-T cell defect is magnified 4-fold after irradiation
compared to steady state. Thus, Zmiz1 is recruited to urgently restore T-cell immunity after cytoreduction. The
Zmiz1 pathway might also have therapeutic utility as supraphysiological activation of Zmiz1 expanded pre-T
cells and primitive early thymic progenitors (ETPs) in vitro. ETPs were expanded as Zmiz1 restrains Notch-
induced T-cell differentiation signals, thereby protecting ETPs from excessive differentiation. Here, our
objective is to understand these novel stage-specific roles of Zmiz1. Our hypothesis is that activating the Zmiz1
pathway induces stage-specific transcriptional programs that promote pre-T cell proliferation and ETP
maintenance. To test this, we will determine how Zmiz1 is induced during thymic regeneration and how Zmiz1
facilitates transcription factor activities by remodeling chromatin. We will also determine how Zmiz1
manipulates cofactors and target genes to promote undifferentiated ETP proliferation. Finally, we will raise
Zmiz1 signals to supraphysiological levels to enhance thymic recovery in vivo. Infection due to prolonged T-cell
deficiency after various cancer therapies is a major clinical problem. Pan-Notch activation as a strategy to
regenerate the T-lineage is problematic. Supraphysiological Notch activation depletes ETPs by promoting
excessive T-cell commitment. In contrast, Zmiz1 preserves ETP cells, promotes proliferation, and by itself
cannot induce leukemia. Thus, our project is significant because it will elucidate a direct Notch1 cofactor that
drives leukemia and plays important stage-specific roles in enhancing early T-cell proliferation while restraining
differentiation. We will learn ...

## Key facts

- **NIH application ID:** 10169233
- **Project number:** 5R01AI136941-03
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** MARK Y CHIANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $508,593
- **Award type:** 5
- **Project period:** 2019-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10169233

## Citation

> US National Institutes of Health, RePORTER application 10169233, Stage-specific roles for Zmiz1 in Notch-dependent steps of early T-cell development (5R01AI136941-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10169233. Licensed CC0.

---

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