# Identifying/Targeting Mechanisms of Lymphomagenesis Driven by CREBBP Inactivation

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2020 · $340,445

## Abstract

Project Summary / Abstract
Follicular lymphoma (FL) is an incurable malignancy of germinal center B-cells, in which sequential relapses
originate from a tumor cell progenitor with a small number of genetic alterations. We recently defined inactivating
mutations of a histone acetyltransferase gene, CREBBP, as an early event in disease genesis following
translocation of the BCL2 oncogene. CREBBP inactivation in primary FL tumors silenced a germinal center B-
cell transcriptional program that was significantly enriched for genes involved in antigen presentation on MHC
class II and targets of the YY1 transcription factor. Reduced antigen presentation was associated with a
decreased ability of tumor cells to activate CD4 T-cell proliferation and a reduced number of T-cells within the
tumor microenvironment. CREBBP epigenetically regulates gene expression via histone acetylation that is
directed via interactions with transcription factors such as CIITA, a central regulator of MHC class II gene
expression, and YY1, a key regulator of germinal center B-cell development. We therefore hypothesize that
inactivating mutations of CREBBP plays dual roles in promoting lymphomagenesis by driving immune evasion
via decreased antigen presentation, and by deregulating B-cell development to allow stalling at the germinal
center B-cell stage. To investigate this, we have developed in vitro and in vivo models of CREBBP inactivation
using CRISPR-modification of lymphoma cell lines and transgenic mouse models, respectively. Importantly,
CRISPR-modified cell lines recapitulate the phenotype of reduced MHC class II expression observed in primary
FL tumors, and transgenic mouse models develop FL-like tumors when Crebbp is deleted and Bcl2 is over-
expressed specifically within B-cells. We will use these models, in parallel with primary human tumors, to explore
the hypothesized mechanistic roles of CREBBP inactivation in lymphomagenesis. Specifically, we will evaluate
the capacity for CREBBP inactivation to reduce antigen presentation on MHC class II, and measure the effect
that this has on T-cell responses in vitro and in vivo. In addition, we will investigate the role of CREBBP
inactivation in reducing the expression of germinal center B-cell genes that are regulated by the YY1 transcription
factor, and determine whether this leads to stalled differentiation at the germinal center B-cell stage in vivo using
transgenic mouse models. We further hypothesize that these phenotypes are driven by epigenetic alterations,
and may therefore potentially be corrected using epigenetic modifying drugs. We will therefore investigate the
potential for HDAC inhibitors and EZH2 inhibitors to restore antigen presentation and associated T-cell
responses, and to reestablish normal epigenetic and transcriptional programs of B-cell development. Together
this work will provide validation for CREBBP inactivation as a key event in the development of FL, define the
mechanism by which these genetic ...

## Key facts

- **NIH application ID:** 9961544
- **Project number:** 5R01CA201380-05
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Michael Richard Green
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $340,445
- **Award type:** 5
- **Project period:** 2016-08-04 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9961544

## Citation

> US National Institutes of Health, RePORTER application 9961544, Identifying/Targeting Mechanisms of Lymphomagenesis Driven by CREBBP Inactivation (5R01CA201380-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9961544. Licensed CC0.

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