Hypomethylating agents (HMA) are currently used as a first-line treatment for patients with myelodysplastic syndrome (MDS) - a group of disorders where there is insufficient production of healthy mature blood cells in the bone marrow - 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 HMA can and does activate the oncofetal protein, SALL4.
The study, which was also conducted in collaboration with University of Tor Vergata in Rome, Italy, and the Institute of Hematology and Blood Diseases Hospital, Tianjin, China, was published in scientific journal New England Journal of Medicine on 26 May 2022.
Turning on the gene that causes cancer
SALL4 is a known oncogene, and expression of SALL4 has been found to contribute to the development of MDS and leukemia. A study conducted by another research group in 2016 had demonstrated that SALL4 activation in a liver cancer cell line was associated with hypomethylation, and Professor Daniel Tenen from CSI Singapore and his team had demonstrated in 2021 that the hepatitis B virus-induced SALL4 demethylation in liver cancer through an RNA mediated mechanism. To examine possible upregulation of oncogenes in patients being treated with hypomethylating agents, Prof Tenen's team collaborated with the other groups to study the association between HMA utilized and SALL4 activation, as well as the implications on survival outcomes.
The research team analyzed the bone marrow samples of 68 patients with MDS, taken before and after their HMA treatment. The scientists found that HMA therapy could result in the activation of the SALL4 oncogene, leading to poor survival outcome for patients, even those in complete disease remission.
Our findings from this pioneering study show that treatment using hypomethylating agents can activate and upregulate oncogenes, such as SALL4. This suggests the importance of monitoring SALL4 expression levels in patients receiving HMA therapy. While upregulation of SALL4 may likely influence the disease progression and be associated with a poorer diagnosis, it may also provide an opportunity to identify patients for early intervention with a drug targeting SALL4 pathways, thereby improving treatment and patient outcomes."
Professor Daniel Tenen from CSI Singapore
Early intervention for better results
Interestingly, these findings by Prof Tenen's group, working with the BWH and HMS teams, further support another study of theirs in 2021, in which they demonstrated that cancer cells with reactivated SALL4 by hypomethylation were efficiently treated with a drug designed to inhibit a SALL4 downstream pathway. These newly established principles may help alter the treatment paradigm for other cancers and diseases where HMA are being used.
Moving forward, the team intends to carry out larger prospective studies to validate these findings and develop low cost but accurate biomarkers kits to monitor SALL4 expression. Through collaborative research across laboratories, the team aims to develop more effective and specific drugs that target SALL4 directly.
Liu, Y-C., et al. (2022) Demethylation and Up-Regulation of an Oncogene after Hypomethylating Therapy. New England Journal of Medicine. doi.org/10.1056/NEJMoa2119771.