Hypomethylating agents Could Activate "Sleeping" Cancer-Causing Gene: NEJM

China: Hypomethylating agents (HMA) are currently used as a first-line treatment for patients with myelodysplastic syndrome (MDS) -and increasingly in other diseases, but their mechanism of action remains unclear. One potential risk is that they could potentially activate a sleeping oncogene, although this has not been clearly demonstrated to date.

In a recent study, scientists from the Cancer Science Institute of Singapore (CSI Singapore) at the National University of Singapore (NUS), working in close collaboration with the Brigham and Women's Hospital (BWH), and the Harvard Medical School (HMS) in Boston have established that Hypomethylating agents can and do activate the oncofetal protein, SALL4.

The study has been published in The New England Journal of Medicine.

Although hypomethylating drugs are now utilized to treat cancer patients, it is unclear if they can also reactivate and up-regulate oncogenes. The researchers investigated the effect of hypomethylating drugs on SALL4, a well-known oncogene involved in myelodysplastic syndrome and other malignancies.

Paired bone marrow samples from two cohorts of myelodysplastic syndrome patients before and after therapy with a hypomethylating drug were used to investigate the associations between changes in SALL4 expression, treatment responsiveness, and clinical prognosis. To investigate the link between SALL4 methylation and expression, leukemic cell lines with low or undetectable SALL4 expression were employed. CRISPR–DNMT1-interacting RNA (CRISPR-DiR), a locus-specific demethylation technique, was utilized to locate the CpG island required for SALL4 expression.