Credit: Darren Baker
Researchers have identified an enzyme that appears key to prognosis and progression in multiple myeloma (MM).
The group found the enzyme, ST3GAL6, is overexpressed in MM cell lines and patients with disease.
This overexpression increases glycosylation, which escalates the interaction between MM cells and selectins.
And this encourages the circulation and spread of MM cells, as well as their retention in the bone marrow.
The researchers recounted this series of events in Blood.
“[W]e focused on alterations in [glycosylation] because of its role in cell-cell interactions and the spread of cancer cells in the blood,” said study author Michael O’Dwyer, MD, of National University of Ireland, Galway.
Using gene set enrichment analysis, he and his colleagues confirmed the overexpression of glycosylation-related signatures in MM. They also discovered the sialyltransferase ST3GAL6 was “one of the most significantly increased genes” in MM patients, when compared to healthy donors.
The team observed increased ST3GAL6 levels in both relapsed and newly diagnosed MM. And they found that higher ST3GAL6 levels were associated with decreased survival.
To expand upon these findings, the researchers went on to test 5 MM cell lines—MM1S, MM1R, U266, RPMI-8226, and H929. They found significantly higher levels of ST3GAL6 mRNA and protein in the cell lines compared to healthy CD138+ cells.
Knocking down ST3GAL6 in 2 of the cell lines—MM1S and RPMI-8226—significantly reduced the amount of alpha 2,3 sialic acid at the cell surface, which suggests that ST3GAL6 contributes to the synthesis of this glycan.
In addition, knocking down ST3GAL6 significantly reduced MM cells’ adhesion to bone marrow stem cells, human umbilical vein endothelial cells, and fibronectin. It also reduced MM cells’ transendothelial migration, attenuated Src activation in MM cells, and reduced the cells’ ability to roll on p-selectin.
Likewise, in mouse models, knockdown of ST3GAL6 reduced MM cell homing and engraftment. It also significantly decreased tumor burden and increased survival in the mice.
The researchers concluded that these findings highlight the importance of altered glycosylation, particularly sialylation, in MM cell adhesion and migration.
“Our research is crucial because it sheds new light on the biology of [MM], which could lead to new strategies to overcome resistance to treatment,” Dr O’Dwyer said. “Our aim now is to prevent these interactions that cause the spread [of MM cells] using specific enzyme and selectin inhibitors.”
