By Alice McCarthy
A recent paper published in New England Journal of Medicine reveals that treatment of myelodysplastic syndrome (MDS) with hypomethylating agents (HMAs) activates a sleeping oncogene, leading to poorer survival. This discovery raises the possibility that early treatment with anti-SALL4 pathway agents could influence the outcomes of HMA-treated patients.
HMAs are currently used as a first-line treatment for patients with MDS - a group of disorders where there is insufficient production of healthy mature blood cells in the bone marrow - and increasingly in other diseases. Scientists have considered that these drugs may potentially activate a sleeping oncogene, although this had not been demonstrated before. To test this theory, investigators from the Brigham and Women’s Hospital in Boston, Harvard Stem Cell Institute, and the Cancer Science Institute of Singapore studied how HMA affects known oncogenes.
The research team analysed the bone marrow samples of 68 patients with MDS, taken before and after HMA treatment. The scientists discovered that HMAs activate the oncofetal protein SALL4 in up to 40 percent of patients with MDS, leading to poor survival outcomes even among 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,” said Daniel Tenen, MD, head of the Blood Program of the Harvard Stem Cell Institute and Director, Cancer Science Institute of Singapore. This suggests the importance of monitoring SALL4 expression levels in patients receiving HMA therapy. While upregulation of SALL4 may be associated with a poorer diagnosis, it may also provide an opportunity to identify patients for early intervention.
“Our data suggest that MDS patients receiving HMA treatment should be monitored for oncogene such as SALL4 demethylation and upregulation for poor outcomes, and provide an additional combination therapy,” said study lead author Li Chai, MD, of the Brigham’s Department of Pathology.
In earlier results in 2021, the research team demonstrated that cancer cells with reactivated SALL4 were treated successfully 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 HMAs are used.
Moving forward, the team intends to conduct larger prospective studies to validate these findings and develop low cost but accurate biomarkers kits to monitor SALL4 expression. They also aim to develop more effective and specific drugs that target SALL4 directly.
Liu, et al. (2022). Demethylation and up-regulation of an oncogene after hypomethylating therapy. The New England Journal of Medicine. DOI: 10.1056/NEJMoa2119771