By Sucharita Mistry, PhD
B-cell lymphomas such as diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) are blood cancers of the immune cells. A vast majority of B-cell lymphomas typically display a high frequency of genetic alterations. Since lymphomas show remarkable genetic diversity, a big challenge for scientists is not only to determine which genes are mutated in these diseases, but also to identify “actionable” genetic alterations that can respond to targeted therapies.
“Discovering how different mutations are involved in causing the disease is a major key to advancing novel mechanism-based precision therapies and immunotherapies for lymphomas, with potentially less toxic side-effects,” says Dr. Ari Melnick, a world-renowned physician-scientist at Weill Cornell Medicine.
Dr. Melnick led groundbreaking research that defines the genetic underpinnings of CREBBP mutation in lymphomas, paving the way for new therapeutic avenues. The findings of this study were recently published in Cancer Discovery.
The CREBBP gene encodes a kind of histone acetyltransferase (HAT), an enzyme that introduces small chemical tags called acetyl groups on histones, which are the major structural proteins of chromosomes. The chemical modifications on histones are termed as epigenetic changes, and they determine whether genes are turned on or off. The CREBBP gene, which is an epigenetic modifier, is frequently mutated in DLBCL and FL.
The Melnick research team, in collaboration with scientists at the MD Anderson Cancer Center, characterized the functional consequences of CREBBP mutation in lymphomas. Using a powerful CRISPR gene-editing technology, the researchers engineered lymphoma cell lines that differed only in the CREBBP mutation status. The research team discovered two different types of CREBBP mutations that either truncate the protein or inactivate the HAT domain, the latter associated with poor clinical outcomes.
This study showed that CREBBP mutation disrupts key biological pathways resulting in abnormal silencing of tumor-suppressive and antigen-presenting pathway genes. This disruption allows lymphoma cells to hide from the immune system so that they cannot be recognized and attacked by the T-cells that play an essential role in the body’s immune response.
More importantly, the malfunction in immune surveillance was restored by an HDAC3 inhibitor, a drug that specifically reverses the histone acetylation defect caused by CREBBP mutation. Notably, selective inhibition of HDAC3 reversed the epigenetic abnormalities, halted lymphoma growth and induced the expression of major histocompatibility (MHC) class II protein, enabling the T cells of the immune system to recognize and kill lymphoma cells. The research team also demonstrated that combination of an HDAC3 inhibitor with an immune checkpoint inhibitor (PD-1/PD-L1 blockade) results in synergistic anti-lymphoma immunity effects.
These findings uncover a novel mechanistic link between CREBBP mutation and immune surveillance dysfunction in lymphomas that can be counteracted by an HDAC3 inhibitor, providing a potentially game-changing approach for restoring anti-tumor immunity.
“HDAC3 inhibition provides an attractive therapeutic avenue for DLBCL and FL and may have enhanced potency in CREBBP-mutant tumors,” says Dr. Melnick. “We are very excited to translate this research into clinical trials that could potentially lead to the development of novel mechanism-based immune epigenetic therapy for CREBBP-mutant lymphomas.”