# Notch and GATA-3 as novel therapeutic targets in T-cell lymphomas

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $349,713

## Abstract

Project Abstract
Rapid disease progression and chemotherapy resistant disease are frequently observed among the most
common T-cell lymphomas (TCL) and the majority of these patients will ultimately succumb to progressive
disease within three years of diagnosis. Only a minority (≤10%) of patients will achieve a durable remission
with novel agents, as the mechanisms promoting TCL progression and chemotherapy resistance are poorly
understood and therapeutic strategies to overcome them are not defined. We have recently shown that the T-
cell transcription factor GATA-3 identifies a molecularly, genetically, and clinically distinct subset of TCL that
are highly resistant to chemotherapy. We have also demonstrated that Notch activation is prevalent in the TCL,
and Notch blockade inhibits both TCL proliferation and GATA-3 expression, a Notch target gene, in preliminary
studies. Genetic and pharmacologic loss-of-function (and gain-of-function) strategies were performed in
genetically diverse TCL cells and subsequently demonstrated that GATA-3 directly confers resistance to
chemotherapy in a cell-autonomous fashion. In addition, lymphoma-associated macrophages (LAM) within the
tumor microenvironment (TME) promote chemotherapy resistance, and GATA-3 dependent cytokines regulate
their functional polarization, highlighting an additional non-cell-autonomous mechanism for GATA-3-dependent
chemotherapy resistance. Thus, there is a critical need to identify factors regulating GATA-3 expression and
function in these aggressive TCL. In the absence of such knowledge, the development of therapeutic
strategies that impair GATA-3-dependent transcriptional regulation and improve outcomes among these TCL
will remain elusive. Our long-term goals are to understand the fundamental mechanisms that drive TCL
pathogenesis and promote their resistance to currently available therapies. In doing so, we hope to develop
rationally designed therapeutic strategies that will overcome the challenge of chemotherapy resistance and
improve outcomes for patients afflicted with these TCL. Our overall objectives in this application are to evaluate
the role of Notch signaling in T-cell lymphomagenesis and to identify the requirements for optimal GATA-3
DNA binding and transcriptional regulation. These will be achieved by addressing our central hypothesis that
Notch and GATA-3 promote TCL progression and resistance to chemotherapy. In addition to being well-
grounded in our own preliminary data, our central hypothesis is entirely consistent with our current
understanding of the genetic landscape and molecular pathogenesis of the TCL and has significant therapeutic
implications.

## Key facts

- **NIH application ID:** 10318634
- **Project number:** 5R01CA236722-03
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Ryan A Wilcox
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $349,713
- **Award type:** 5
- **Project period:** 2019-12-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10318634

## Citation

> US National Institutes of Health, RePORTER application 10318634, Notch and GATA-3 as novel therapeutic targets in T-cell lymphomas (5R01CA236722-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10318634. Licensed CC0.

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