Blunted CD40-Responsive Enhancer Activation in CREBBP-Mutant Lymphomas Can Be Restored by Enforced CD4 T-Cell Engagement

Authors

Haopeng Yang
Wenchao Zhang
Vida Ravanmehr
Guiling Cui
Kevin Bowman
Ruidong Chen
Jared M Henderson
Shyanne Lockman
Estela Rojas
Ashley Wilson
Sydney Parsons
Ariel Mechaly
Leslie Regad
Ahmed Haouz
Christopher R Flowers
Sattva Neelapu
Loretta Nastoupil
R Eric Davis
Qing Deng
Fernando Rodrigues-Lima
Michael R Green

Publication Date

7-10-2025

Journal

Blood

DOI

10.1182/blood.2024026664

PMID

40090010

Abstract

The CREBBP lysine acetyltransferase (KAT) is frequently mutated in follicular lymphoma and diffuse large B-cell lymphoma and has been studied using gene knockout in murine and human cells. However, most CREBBP mutations encode amino acid substitutions within the catalytic KAT domain (CREBBP KAT-PM) that retain an inactive protein and have not been extensively characterized. Using CRISPR gene editing and extensive epigenomic characterization of lymphoma cell lines, we found that CREBBP KAT-PM lead to unloading of CREBBP from chromatin, loss of enhancer acetylation, and prevention of EP300 compensation. These enhancers were enriched for those that are dynamically loaded by CREBBP in the normal centroblast-to-centrocyte transition in the germinal center, including enhancers activated in response to CD40 signaling, leading to blunted molecular response to CD40 ligand in lymphoma cells. We provide evidence that CREBBP KAT-PM inhibits EP300 function by binding limiting quantities nuclear transcription factor (TF), thereby preventing its compensatory activity. This effect can be experimentally overcome by expressing saturating quantities of TF or biologically attenuated by strong stimulation of CD40 signaling that increases nuclear TF abundance. Importantly, epigenetic responses to CD40 signaling can be induced by enforcing CD4 T-cell engagement using a bispecific antibody, leading to CD40-dependent restoration of antigen presentation machinery in CREBBP KAT-PM cells and cell death. Therefore, we provide a mechanistic basis for enhancer deregulation by CREBBP KAT-PM and highlight enforced CD4 T-cell engagement as a potential approach for overcoming these effects.

Keywords

CREB-Binding Protein, Humans, Enhancer Elements, Genetic, E1A-Associated p300 Protein, CD4-Positive T-Lymphocytes, Cell Line, Tumor, CD40 Antigens, Mutation, Animals, Mice, Lymphoma, Signal Transduction, Acetylation, Lymphoma, Large B-Cell, Diffuse

Published Open-Access

yes

Recommended Citation

Yang, Haopeng; Zhang, Wenchao; Ravanmehr, Vida; et al., "Blunted CD40-Responsive Enhancer Activation in CREBBP-Mutant Lymphomas Can Be Restored by Enforced CD4 T-Cell Engagement" (2025). Faculty, Staff and Student Publications. 4335.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/4335