# Epigenetic Mechanisms Underpinning Mantle Cell Lymphoma Sensitivity and Resistance to Notch Inhibitors

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $420,829

## Abstract

Project Summary
Gain-of-function Notch mutations are among the most frequent mutations in small B cell lymphomas, including
chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). Harboring Notch mutation is also a
predictor of poor outcomes in small B cell lymphomas, which despite recent advances remain incurable with
chemotherapy. Together, these observations provide a compelling rationale for focusing on Notch inhibitors as
potential therapeutic options in small B cell lymphomas. Unfortunately, progress in treating patients with Notch
inhibitors has been stymied partly due to a limited understanding of underlying mechanisms of sensitivity and
resistance to Notch inhibitors. Here, we represent a concerted effort to overcome these limitations and fill major
gaps in current knowledge by testing our central hypothesis that Notch-driven activation and positioning of
enhancers synergize Notch and several crucial signaling pathways to co-activate pro-growth and survival genes
in small B cell lymphomas. This premise is based on our preliminary data showing an important consequence of
Notch inhibition is decommissioning and repositioning of putative enhancer elements associated with key genes
in primary small B cell lymphoma samples, including several components of B cell receptor (BCR) and cytokine
signaling pathways. We will test this hypothesis by using cutting-edge functional genomics, chromatin
conformation capture, genome engineering, and single-cell resolution genomics and optical assays. We will
systematically determine: i) the Notch-dependent enhancer activation and nuclear positioning, and their genomic
requirements that together mediate crosstalk between Notch, BCR and cytokine signaling pathways; ii) the
rewiring of Notch-driven epigenetic program that enables drug-resistant cells to bypass effects of Notch inhibitors
and maintain the expression of critical Notch targets. Together, these complementary studies will greatly expand
understanding of epigenetic mechanisms underpinning sensitivity and resistance to Notch inhibitors and provide
a clearer rationale for targeting Notch in small B cell lymphoma.

## Key facts

- **NIH application ID:** 10445457
- **Project number:** 1R01CA248041-01A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Robert Babak Faryabi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $420,829
- **Award type:** 1
- **Project period:** 2022-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10445457

## Citation

> US National Institutes of Health, RePORTER application 10445457, Epigenetic Mechanisms Underpinning Mantle Cell Lymphoma Sensitivity and Resistance to Notch Inhibitors (1R01CA248041-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10445457. Licensed CC0.

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