A research team led by the UF Health Cancer Center has identified a novel mechanism in the epigenome that could pave the way to develop new therapies for multiple myeloma.
The research, published recently in the American Society of Hematology’s journal Blood, was led by the lab of Jonathan D. Licht, M.D., director of the UF Health Cancer Center.
Multiple myeloma is the second most common blood malignancy. The prognosis for patients has improved over the years with therapies targeting specific characteristics of the plasma cell. Still, most patients eventually relapse because they acquire resistance to existing drugs. Researchers are working to develop personalized therapies that target vulnerabilities arising from specific genetic lessons.
In about 15% of patients with multiple myeloma, the histone methyltransferase NSD2 is overexpressed because of chromosomal translation (4;14) and is associated with a poor prognosis. In the new study, the team used CRISPR screening to search the genome for genes that are essential for multiple myeloma cell survival when NSD2 is overexpressed.
This led them to identify the mitochondrial enzyme adenylate kinase 2 (AK2) as a selective liability for myeloma cells that overexpress NSD2. The researchers found that targeting AK2 in these cells disrupted mitochondrial energy distribution, induced DNA replication stress, and enhanced sensitivity to proteasome inhibitors, a class of drugs used to treat the disease.
In multiple myeloma cells, overexpression of NSD2 diverts the one-carbon metabolite S-adenosylmethionine to the epigenome, disrupting the ability of cells to synthesize creatine. When creatine is depleted, the cells become hypersensitive to the loss of AK2.
“Our findings present AK2 as a novel therapeutic target for multiple myeloma, especially in patients with t(4;14) chromosomal translocations,” the researchers wrote.
Amin Sobh, a postdoctoral fellow in Licht’s lab, was the first author of the study, which involved researchers at Northwestern University, Emory University School of Medicine, the University of Texas Health Science Center San Antonio, Winship Cancer Institute, and Dana-Farber Cancer Institute.
Shared resources in bioinformatics, cytometry, gene expression, and next-generation sequencing available through the UF Health Cancer Center and the UF Interdisciplinary Center for Biotechnology Research facilitated the discovery. The study received funding from the Florida Department of Health, Leukemia and Lymphoma Society, Myeloma Solutions Fund, American Association for Cancer Research, National Institutes of Health, and the Paula and Roger Riney Foundation. The UF Health Cancer Center receives crucial support for its research from the Casey DeSantis Cancer Research Act (Fla. Stat. § 381.915).
