Treatment of myelodysplastic syndrome by hyp

Hypomethylating agents (HMAs) are currently used as first-line treatment for patients with myelodysplastic syndrome (MDS), and increasingly in other diseases, but their mechanism of action is unclear. HMAs can affect many genes and could potentially activate an oncogene – a gene that contributes to the development of cancer – but this has not been clearly demonstrated to date. To test this, researchers 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, resulting in poor patient survival, even in patients in clinical remission. The results may apply to other cancers and diseases in which HMAs are used.

“SALL4 is an embryonic stem cell (ES) gene and a leukemic stem cell factor, and it belongs to a new class of oncofetal gene. Gain-of-function SALL4 transgenic mice develop MDS and acute myeloid leukemia (AML), as well as liver tumors. Loss-of-function studies have demonstrated that SALL4 is essential for the survival of cancer cells, including leukemic cells, by regulating several survival pathways. Our data suggest that patients with MDS receiving HMA treatment should be monitored for demethylation and upregulation of oncogenes such as SALL4, which we believe are linked to poor outcomes, and these patients should receive additional combination therapy. said lead author Li Chai, MD, of Brigham’s Department of Pathology.

The Chai lab has been working on SALL4 since 2003, and Chai has led a research program focused on the function, mechanism, structure, and targeting of SALL4. Given the unique oncofetal expression pattern of the gene, she and her collaborators pioneered a breakthrough SALL4-based approach to classify and target cancer, and their previous work demonstrated the feasibility of targeting this ES cell gene in cancers ( Yong KJ, et al NEJM, 2013, Liu B, et al PNAS, 2018, Yang J, et al Cancer Research, 2021).

Learn more in The New England Journal of Medicine.


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