Treatment with an inhibitor of the epigenetic enzyme SETD8 may be a novel therapeutic option to overcome melphalan resistance in patients with multiple myeloma (MM), according to research published in Clinical Epigenetics.

Most patients with MM eventually relapse or develop drug resistance despite treatment advances that have improved survival rates.

SETD8, an epigenetic enzyme responsible for the monomethylation of histone H4 at lysine 20 (H4K20), is associated with poorer prognosis with MM and inhibition of SETD8 may offer new treatment options.

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Study authors used MM cells lines and bone marrow plasma cells to identify epigenetic factors in multiple myeloma. Analyses found that SETD8 expression was higher in multiple myeloma cells from patients who relapsed than in newly diagnosed patients, suggesting that SETD8 may play a role in drug resistance.

“Altogether, these data reveal that the epigenetic enzyme SETD8 is overexpressed in myeloma and this up-regulation is associated with a poor outcome and deregulation of major signaling pathways in MM patients,” the authors wrote in their report.

The authors also evaluated UNC-0379, a small molecule inhibitor of SETD8, and found that UNC-0379 leads to growth inhibition and death of malignant plasma cells. The cytotoxicity induced by UNC-0379 does not appear to be dependent on p53 status. Both p53 wild-type and deficient MM cells showed similar response to SETD8 inhibition.

Further, the authors analyzed whether the cytotoxic effects of UNC-0379 could improve treatment with melphalan, a common treatment for multiple myeloma. Results showed that UNC-0379 enhanced the cytotoxic effects of melphalan regardless of p53.

Altogether, upregulation of SETD8 was associated with a poorer prognosis and the deregulation of major signaling pathways based on analysis of MM cell lines. Inhibiting this enzyme may present a novel therapeutic option to overcome melphalan resistance.


Herviou L, Ovejero S, Izard F, et al. Targeting the methyltransferase SETD8 impairs tumor cell survival and overcomes drug resistance independently of p53 status in multiple myeloma. Clin Epigenetics. 2021;13(1):174. doi:10.1186/s13148-021-01160-z