# Development of first-in-class histone acetyltransferase (HAT) activators for precision targeting of epigenetic derangements in lymphoma

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2022 · $370,575

## Abstract

Diffuse large B-cell lymphoma (DLCBL) is the most common type of lymphoma affecting ~30,000 patients
annually. Recent insights into the molecular pathogenesis of DLBCL has divided this disease into two molecular
subtypes: germinal center (GC) and ABC subtypes. Targeting molecular features of ABC-DLCBL are in the final
stages of development, but such success has not been realized for the more common GC-DLCBL. The GC is a
compartment of the lymph node responsible for generating high affinity antibodies via somatic hyper-mutation
and class switch recombination. Epigenetic modifiers such as EZH2, histone acetyltransferases (HATs), and the
transcriptional repressor, Bcl6, are essential to B-cell development allowing for requisite mutagenesis and silencing
of tumor suppressors necessary for somatic hypermutation. This physiologic state is partly achieved by
decreased acetylation and increased methylation of histones enforcing a transcriptionally repressed state.
Mutations affecting these epigenetic and transcriptional modifiers, HATs, EZH2 and Bcl6, have been identified as
driving events in GC-derived lymphomas.
 Given the critical importance of epigenetic dysfunction in the pathogenesis of GC-derived B-cell lymphomas,
we hypothesize that if inactivating mutations in HAT alleles are crucial to GC-DLBCL then drugs activating the
wild-type enzyme should demonstrate therapeutic effect. In addition, we believe that combined targeting of
epigenetic machinery with HAT activators and other epigenetic modifying agents (HDAC and EZH2 inhibitors)
may induce profound epigenetic modification leading to synergistic induction of programmed cell death. Finally,
if mutational status and expression levels of specific genes such as EP300 correlate with response to HAT
activators or combined epigenetic therapy, then a NanoString expression panel may be developed as a
biomarker for response.
 The objectives of this proposal will be evaluated by addressing the following specific aims: (1) Characterize
the HAT activator YF2 by determining binding to HAT enzymes and its functional effects on acetylation in cell-
free assays. (2) Determine the effects of HAT activators in combination with clinically available epigenetic
modifying agents in cell lines and mice. Epigenetic modifying agents will include HDAC and EZH2 inhibitors.
The effects of HAT activators in combination with epigenetic modifying agents on post-translational
modifications (methylation, acetylation), and gene expression of downstream targets will be determined. (3)
Interrogate the mutational status of EP300 and epigenetic gene signatures of lymphoma cell lines to inform precision
targeting with HAT activators. Basal gene mutation and expression profiles will be determined for candidate
epigenetic and transcriptional modifiers in lymphoma cell lines and will be correlated to the IC50 of HAT activators
and the synergy coefficients of combined epigenetic therapy. Should we accept these hypotheses, this would
repre...

## Key facts

- **NIH application ID:** 10470919
- **Project number:** 5R01CA222931-05
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Jennifer E. Amengual
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $370,575
- **Award type:** 5
- **Project period:** 2018-09-21 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10470919

## Citation

> US National Institutes of Health, RePORTER application 10470919, Development of first-in-class histone acetyltransferase (HAT) activators for precision targeting of epigenetic derangements in lymphoma (5R01CA222931-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10470919. Licensed CC0.

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