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.

The key findings of this study were as follows:

1. SALL4 upregulation following hypomethylating drug therapy was detected in 10 of 25 patients (40%) in cohort 1 and 13 of 43 patients (30%) in cohort 2, and was linked with a poorer prognosis.

2. Researchers observed that demethylation of a CpG island inside the 5′ untranslated region was required for SALL4 expression using CRISPR-DiR.

3. They demonstrated that treatment with a hypomethylating drug resulted in demethylation of the same CpG site and up-regulation of SALL4 expression in cell lines and patients.

In conclusion, treatment with a hypomethylating drug resulted in demethylation of the same CpG site and elevation of SALL4 expression in cell lines and patients. They are now investigating the possibility of adding a concurrent targeted medication that directly or indirectly mitigates SALL4 expression, function, or both to the treatment plan if SALL4 expression is elevated.

Reference:

Liu, Y.-C., Kwon, J., Fabiani, E., Xiao, Z., Liu, Y. V., Follo, M. Y., Liu, J., Huang, H., Gao, C., Liu, J., Falconi, G., Valentini, L., Gurnari, C., … Chai, L. (2022). Demethylation and up-regulation of an oncogene after hypomethylating therapy. New England Journal of Medicine, 386(21), 1998–2010. https://doi.org/10.1056/NEJMoa2119771