UF Health Cancer Center researchers have discovered an important role of a protein in regulating genes that affect the immune system response to multiple myeloma.
The team found that the protein, histone H3K27 demethylase KDM6A, binds and regulates genes that determine how immune cells are activated to target cancerous cells.
The study, led by the laboratory of UF Health Cancer Center Director Jonathan D. Licht, M.D., was published recently in the American Society of Hematology’s journal Blood.
Despite significant advances in treatment strategies, multiple myeloma remains an incurable disease and accounts for 20% of all deaths from blood cancers. About a quarter of patients with multiple myeloma have mutations in genes involved in the control of genetic expression. These affected genes include KDM6A.
More than one third of all multiple myeloma cell lines have abnormalities in KDM6A, and most of these cells are from advanced cases of the disease. That suggests that the loss of the protein may be a factor in disease progression.
In the new study, the researchers set out to understand the function of KDM6A in multiple myeloma using CRISPR-engineered cell lines and genome-wide sequencing techniques.
They found that KDM6A bound at sites in the DNA close to genes that regulate immune function. They also found that depletion of the protein led to a decrease in activity at these key sites.
The research team also conducted studies in mouse cells, finding that a loss of Kdm6a led to increased tumor growth. That was in part because immune cells were less able to infiltrate the tumor when the protein was lacking.
By using a small compound called an HDAC3 inhibitor to re-establish the protein activity, the researchers were able to restore the expression of the target genes.
“Our work indicates that targeting the epigenetic pathways to restore the ability of the immune system to attack tumors could be a potential therapeutic strategy in multiple myeloma,” said lead author Daphné Dupéré-Richer, Ph.D., a research assistant professor in Licht’s lab.
The team included researchers at Emory University, Dana-Farber Cancer Institute, and collaborators in Spain and Italy. The study was supported in part by the Leukemia & Lymphoma Society Specialized Center of Excellence and National Cancer Institute, among other funding organizations. The UF Health Cancer Center receives crucial support for its research from the Casey DeSantis Cancer Research Act (Fla. Stat. § 381.915).
