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Use of Hypomethylating Agents for MDS May Activate Oncogene

MDS

New research has found that demethylation and up-regulation of an oncogene after treatment with a hypomethylating agent (HMA) can occur and warrants further study.

HMAs are currently used as a first-line treatment for patients with myelodysplastic syndromes (MDS), and increasingly in other diseases, but their mechanism of action is not clear. HMAs may affect many genes and could potentially activate an oncogene, but this has not been clearly demonstrated to date.

To test this, investigators from Brigham and Women’s Hospital, Harvard Stem Cell Institute, and collaborators studied how HMA affects known oncogenes. They found that HMA activated the oncofetal protein SALL4 in up to 40% of patients with MDS, leading to poor patient survival, even in those in clinical remission.

Specifically, the study looked at two cohorts of patients. SALL4 up-regulation after treatment with HMAs occurred in 40% of patients in Cohort 1 and 30% of patients in Cohort 2.

Using CRISPR-DNMT1-interacting RNA, the researchers found that demethylation of CpG island within the 5’ untranslated region was critical for SALL4 expression. Then, using cell lines and patients, they confirmed that treatment with a HMA led to demethylation of the same CpG region and up-regulation of SALL4 expression.

“Our data suggest that MDS patients receiving HMA treatment should be monitored for demethylation and up-regulation 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 lead author Li Chai, MD, of the Brigham’s Department of Pathology.

The findings may apply to other cancers and diseases in which HMAs are being used.

Liu Y-C, Kwon J, Fabiani E, et al. Demethylation and up-regulation of an oncogene after hypomethylating therapy. N Engl J Med. 2022. doi:10.1056/NEJMoa2119771

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