Protein Inhibitor Could be New Approach for Treating Non-Hodgkin Lymphomas

Lymphoma cancer cell, SEM
Lymphoma cancer cell. Coloured scanning electron micrograph (SEM) of a lymphoma cell. A lymphoma is a cell of the immune system that has become cancerous. The cell becomes immortal and can grow indefinitely. A number of these cells will form a tumour. Lymphomas most commonly occur in the lymph nodes and spleen, which are rich in tissue containing lymphocytes, and can spread to the liver and bone marrow. Lymphoma cancers are classified into either Hodgkins lymphoma (presence of Reed-Sternberg cells) or non- Hodgkins lymphoma. Treatment is with chemotherapy and radiation therapy and is often successful. Magnification: x9000 when printed at 10 centimetres high.

A study from researchers at MD Anderson Cancer Center and Weill Cornell Medical School, published today in Cancer Discovery has demonstrated a new approach to treating two of the most common subtypes of lymphoma via manipulation of molecular programs controlled by the cAMP-response element binding protein (CREBBP).

CREBBP mutations are common in in follicular lymphoma and diffuse large B-cell lymphomas (DLBCL) an serve to allow malignant cells to not be detected by the immune system.

In the new study the researcher team, led by Michael Green, Ph.D., assistant professor of Lymphoma & Myeloma at MD Anderson and Ari Melnick, M.D., of Weill Cornell show how inhibition of a protein called histone deacetylase 3 (HDAC3) restores immune programs lost as a result of CREBBP mutations. The findings could potentially lead to new treatment regimens approaches for common forms of non-Hodgkin lymphoma.

“CREBBP mutations are highly recurrent in B-cell lymphomas and either inactivate its histone acetyltransferase (HAT) domain or truncate the protein,” said Green in an MD Anderson press release. “We showed that these two classes of mutations yield different degrees of disruption of the epigenome, with HAT mutations being more severe and associated with inferior clinical outcome.”

CREBBP is the second most frequently mutated chromatin-modifying gene in both follicular lymphoma and DLBCL. It encodes a protein that alters the activity of genes by modifying the histone proteins around which DNA is wrapped.

Using CRISPR/Cas9 gene editing of cell lines and mouse models, the investigators also showed that HDAC3 selective inhibitors reverse aberrant epigenetic programming caused by CREBBP resulting in growth inhibition of lymphoma cells and restoration of immune surveillance.

“Our study characterized the molecular consequences of CREBBP mutations and identified key cellular pathways silenced as a result of unopposed HDAC3 activity,” Green added. “We demonstrated how inhibition of HDAC3 restores these pathways, suppressing growth and most critically enabling T cells to recognize and kill lymphoma cells.”

HDAC3 inhibitors appear to affect expression of major histocompatibility molecular class II (MHC class II), molecules, which are antigen presentation proteins crucial for initiating adaptive immune responses.

“The frequency of MHC class II loss in DLBCL exceeds the frequency of CREBBP mutations in this disease through unknown mechanisms,” said Green. “The ability of HDAC3 inhibition to induce MHC class II expression may have potentially broad implications for immunotherapy. We believe that inhibition of HDAC3 represents a novel mechanism-based immune-epigenetic therapy for CREBBP- mutant lymphomas.

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