Reprogramming the epigenetic code affects growth and survival of tumour cells in multiple myeloma

In the cancer type multiple myeloma, the malignant cells differ significantly from normal cells regarding the layer of chemical “tags” on DNA and proteins that control whether genes are turned on or off. These “tags” affect growth and survival of the tumour cells and could be utilised for developing new treatment strategies against multiple myeloma. This is shown in a recent study from Uppsala University, published in the journal Scientific Reports.

Multiple myeloma is an aggressive blood cancer characterized by the accumulation of malignant plasma cells in the bone marrow. The extensive genetic heterogeneity of the disease often leads to drug resistance to conventional treatments and eventual relapse, underscoring the urgent need for new therapeutic approaches.

Emerging evidence from this group and others has highlighted epigenetic aberrations, i.e mistakes in the chemical tags that control how our genes work, as vital drivers in multiple myeloma pathogenesis. The new study presents a comprehensive map of epigenetic alterations in multiple myeloma, comparing normal plasma cells with malignant counterparts.

“When we compared samples from multiple myeloma patients and healthy donors, we found site-specific increase in DNA and protein methylation at regions in the genome that control gene activity. These epigenetic alterations in the malignant cells affect the activity of genes involved in tumour growth and survival,” says Antonia Kalushkova, researcher at the Department of Immunology, Genetics and Pathology and last author of the study.

Another significant finding was the physical interaction between the enzymes DNMT1 and EZH2 that guide the deposition of identified chemical “tags” in multiple myeloma cells. These enzymes are both epigenetic silencers and their interaction indicates an interplay between them. This prompted the researchers to investigate the effects of simultaneously inhibiting both enzymes.

By treating multiple myeloma cells with a combination of an EZH2 inhibitor and a DNMT inhibitor, the researchers observed extensive epigenomic alterations and prominent anti-tumour effects. This dual inhibition led to both reduced DNA methylation and activation of genes associated with cell death.

"Our findings provide novel insights into the role of epigenetic gene silencing in multiple myeloma tumorigenesis. The physical interaction between DNMT1 and EZH2, coupled with the dramatic anti-tumour effects of their combined inhibition, supports the notion that this dual strategy could potentially provide clinical benefit. This research opens doors for developing new combination strategies to treat multiple myeloma, especially for patients who develop resistance to existing therapies,” says Helena Jernberg Wiklund, corresponding author of the study.