# Notch ligands as oncogenic drivers and therapeutic targets in T-cell lymphomas

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $656,250

## Abstract

Peripheral T-cell lymphomas (PTCL), derived from mature T cells, are aggressive malignancies for which
existing therapies are suboptimal, as the median overall survival of patients with relapsed/refractory disease is
<6 months. These dismal outcomes are explained, at least in part, by an intrinsic resistance to conventional
chemotherapeutic approaches and a poor understanding of recurrent, and therapeutically targetable,
oncogenic drivers. Despite their genetic and molecular heterogeneity, most PTCL remain dependent upon their
microenvironment, as constituents of the tumor microenvironment (TME) promote the growth, survival, and
chemotherapy resistance of malignant T cells through trophic factors. Therefore, improved understanding of
the trophic factors available to PTCL within the TME, and the cells that provide them, may unveil novel
therapeutic strategies.
Notch signaling, triggered by ligands presented by non-hematopoietic stromal cells, plays a critically important
role in the development, differentiation, and function of conventional (non-malignant) T cells. Utilizing relevant
and complementary genetically engineered mouse (GEM) models and primary PTCL specimens, we have
discovered that Notch activation is highly recurrent in PTCL, not otherwise specified (PTCL, NOS). When
activated, Notch signaling is associated with significant transcriptional reprogramming, PTCL proliferation, and
a TME rich in fibroblastic reticular cells (FRC), which are specialized stromal cells required for the presentation
of Notch ligands to conventional T cells in secondary lymphoid organs. Our preliminary data, utilizing
complementary pharmacologic (i.e. antibody-based, and thus clinically translatable) and genetic approaches
demonstrate that Notch signaling is an oncogenic driver in PTCL. Therefore, our overall objective in this
application, bolstered by our preliminary data, is to identify the oncogenic Notch ligand(s) and the stromal cells
that present them, and further characterize the transcriptional programs that they instigate, in PTCL. This
objective will be achieved by addressing our central hypothesis that non-mutational, stromal cell- and ligand-
dependent Notch signaling is a significant and therapeutically targetable oncogenic driver in mature T-cell
lymphomas.

## Key facts

- **NIH application ID:** 10798426
- **Project number:** 1R01CA278976-01A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Ivan Maillard
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $656,250
- **Award type:** 1
- **Project period:** 2024-01-01 → 2028-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10798426

## Citation

> US National Institutes of Health, RePORTER application 10798426, Notch ligands as oncogenic drivers and therapeutic targets in T-cell lymphomas (1R01CA278976-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10798426. Licensed CC0.

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