Hypomethylating agents (HMAs) are currently used as first-line treatments for patients with myelodysplastic syndrome (MDS), and increasingly in other diseases, but their mechanism of action is unclear. HMAs can affect many genes and can potentially activate an oncogene – a gene that promotes cancer – but to date this has not been clearly demonstrated.
To test this, researchers from Brigham and Women’s Hospital, Harvard Stem Cell Institute and staff studied how HMA affects known oncogenes. They found that HMA activated the oncofetal protein SALL4 by up to 40 percent patients with MDS, leading to poor patient survival, even in patients in clinical remission. The findings can be applied to other cancers and diseases that use HMA.
“SALL4 is an embryonic stem cell (ES) gene and a leukemic stem cell factor, and it belongs to a new class of oncofetal genes. Enhanced SALL4 function transgenic mice develop MDS and acute myeloid leukemia (AML) as well as liver tumors. Studies of loss of function have shown that SALL4 is necessary for the survival of cancer cells, including leukemic cells by regulating multiple survival pathways. Our data suggest that patients with MDS receiving HMA treatment should be monitored for demethylation and enhanced regulation of oncogenes such as SALL4, which we have found to be associated with poor outcomes, and these patients should be given adjunctive combination therapy. “,” said lead author Lee Chai, MD, Brigham’s Department of Pathology.
The Tea Lab has been working on SALL4 since 2003, and Tea has led a research program focusing on the functions, mechanisms, structure and targeting of SALL4. Given the unique pattern of oncofetal gene expression, she and her colleagues initiated an innovative SALL4-based approach to cancer classification and targeting, and their previous work has shown the possibility of targeting this ES cell gene in cancer. Current research is in New England Medical Journal.
Demethylation and regulation of the oncogene after hypomethylating therapy, New England Medical Journal (2022). DOI: 10.1056 / NEJMoa2119771
Junyu Yang et al., Targeting inductionally SALL4-mediated cancer vulnerability through sequential therapy, Cancer research (2021). DOI: 10.1158 / 0008-5472.can-21-0030
Bee Hui Liu et al., Targeting cancer dependence for SALL4 by shifting its transcript with a pharmacological peptide, Proceedings of the National Academy of Sciences (2018). DOI: 10.1073 / pnas.1801253115
Kol Jia Yong et al, Oncofetal GeneSALL4 in aggressive hepatocellular carcinoma, New England Medical Journal (2013). DOI: 10.1056 / NEJMoa1300297
Brigham and Women’s Hospital
Citation: Treatment of myelodysplastic syndrome with hypomethylating agents can activate an oncogene (May 26, 2022), received May 26, 2022 from https://medicalxpress.com/news/2022-05-treatment-myelodysplastic-syndrome-agentspomethylating.html
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