HYPOMETHYLATING agents (HMA) currently used to treat patients with cancer may upregulate an oncogene that could reduce the survival rates of patients, according to researchers from Brigham and Women’s Hospital, Massachusetts, USA; Harvard Stem Cell Institute, Massachusetts, USA; and their collaborators in this study. HMAs, such as decitabine and 5-azacytidine, are used in the treatment of myelodysplastic syndrome (MDS), a rare blood cancer. These drugs tend to reactivate tumour growth suppressing genes; however, they may unintentionally activate oncogenes, which activate cancer growth.
In this study, the researchers investigated how HMAs affect the SALL4, a familiar oncogene that plays a significant role in MDS and other cancers. Bone marrow samples that were acquired from two cohorts of patients diagnosed with MDS, before and after treatment with an HMA, were used to investigate the links between changes in the SALL4 oncogene expression, response to treatment, and outcome. They used a locus-specific demethylation technology to observe the SALL4 oncogene expression.
The results showed that up to 40% of patients with MDS had elevated levels of SALL4 expression in their bone marrow after receiving an HMA. The upregulation of this oncogene was linked to the worst clinical outcome. This expression was detected in 10 of 25 patients (40%) in the first cohort and in 13 of 43 patients (30%) in the second cohort. The researchers’ findings showed that HMAs enabled an increased expression of SALL4, by eliminating chemical marks called methyl groups from near the SALL4 gene, which was apparent in these patients. The researchers concluded that these results may be similar to other cancers, such as acute myeloid leukaemia, when HMA is used as treatment.
“Our data suggest that patients with MDS receiving HMA treatment should be monitored for demethylation and upregulation of oncogenes such as SALL4, which we found are linked to poor outcomes, and these patients should be provided with an additional combination therapy,” said Li Chai, Brigham’s Department of Pathology in Boston, Massachusetts, USA, and co-lead of the study.