# Targeting Acetyltransferase Gene Inactivation in Diffuse Large B Cell Lymphoma

> **NIH NIH P50** · SLOAN-KETTERING INST CAN RESEARCH · 2020 · $379,081

## Abstract

Diffuse Large B-cell Lymphoma (DLBCL) represents the most common form of B-cell non-Hodgkin Lymphoma
(B-NHL), accounting for ~30% of de-novo diagnoses and also arising as a frequent clinical evolution of
Follicular Lymphoma (FL). Despite remarkable progress in the treatment of this disease, a significant fraction
of DLBCL remains incurable, underscoring the need to identify molecular mechanisms that are responsible for
disease development and that can be targeted therapeutically. By integrating whole exome sequencing and
high-resolution single nucleotide polymorphism array analysis, we have identified recurrent inactivating
mutations and deletions of CREBBP (CBP) and, more rarely, EP300 (p300) in a large fraction of DLBCL
patients, including 40% of those diagnosed de novo and ~50% of those derived from transformation of FL
(Pasqualucci et al., Nature 2011; Pasqualucci et al., Cell Reports 2014). CBP and p300 are two highly related
histone and non-histone acetyltransferases (HATs) and are involved in multiple signaling pathways by
modulating the activity of several proteins, such as the oncoprotein BCL6, which is typically inactivated by
acetylation, and the tumor suppressor p53, which instead requires acetylation for its function. Defects in CBP
and p300 may therefore play a central role in promoting the development and maintenance of lymphoma cells.
Following on these findings, the general objective of this proposal is to elucidate the normal and pathologic role
of CBP and p300 in B cells, to establish pre-clinical models for their therapeutic targeting, and to test the
activity of the novel HDAC inhibitor Mocetinostat in a phase II clinical trial. The following Specific Aims will be
pursued: 1). Identify the full complement of genetic and epigenetic lesions affecting CBP/p300 in DLBCL, as a
pre-requisite to design an optimal stratification strategy for the clinical trials proposed in Specific Aim 4. 2).
Identify biomarkers of CBP/p300 activity (and loss thereof) by defining the set of genes that are bound by CBP
and whose expression is modulated by CBP/p300 inactivation in GC B cells. 3). Elucidate the role of CBP
inactivation in normal B cell development and transformation, by constructing mutant mice in which CBP is
conditionally inactivated in GC B cells and which could be used as preclinical models for therapeutic testing. 4).
Investigate whether pharmacologic inhibition of specific deacetylases in DLBCL patients with CBP/p300
inactivation predicts improved clinical efficacy of deacetylase inhibitors, either alone or in combination with
other drugs.

## Key facts

- **NIH application ID:** 9988858
- **Project number:** 5P50CA192937-05
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** ANDREW D. ZELENETZ
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $379,081
- **Award type:** 5
- **Project period:** 2016-08-30 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9988858

## Citation

> US National Institutes of Health, RePORTER application 9988858, Targeting Acetyltransferase Gene Inactivation in Diffuse Large B Cell Lymphoma (5P50CA192937-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9988858. Licensed CC0.

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