09 June 2022

An international group of scientists has discovered how a treatment for people with a rare blood cancer could potentially activate an oncogene, and may reduce their chances of survival.

Hypomethylating agents (HMAs), such as decitabine and 5-azacytidine, are used as first-line treatments for patients with myelodysplastic syndrome (MDS). The drugs aim to reactivate genes which supress tumour growth. But HMAs affect many genes, and may inadvertently activate cancer-promoting oncogenes, researchers say.

Now researchers from Brigham and Women’s Hospital, Harvard Stem Cell Institute, and their collaborators, have examined how these agents affect one such oncogene, called SALL4.

Writing in the New England Journal of Medicine, they found that up to 40% of MDS patients had raised levels of SALL4 gene expression in their bone marrow after receiving an HMA. Those with raised SALL4 expression had poorer survival, even in patients in clinical remission.

Further investigation proved that HMAs were able to increase expression of SALL4, by removing chemical marks called methyl groups from near the SALL4 gene. They then showed that the loss of these methyl groups near SALL4 was apparent in MDS patients with increased SALL4 expression, but not in those with reduced SALL4. Combined, these results suggest that HMAs inadvertently increase SALL4 expression in some patients, leading to reduced chances of survival.

They say these findings could also apply to other cancers and diseases if HMAs are used as treatments.

Dr Li Chai from Brigham’s Department of Pathology in Boston, who co-led the research, said: “Gain-of-function SALL4 transgenic mice develop MDS and acute myeloid leukaemia (AML), as well as liver tumours. Loss-of-function studies demonstrated that SALL4 is essential for the survival of cancer cells, including leukemic cells by regulating multiple survival pathways.

“Our data suggest that MDS patients 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.”

Source: Liu YC, Kwon J, Fabiani E, Xiao Z, Liu YV, Follo MY, Liu J, Huang H, Gao C, Liu J, Falconi G, Valentini L, Gurnari C, Finelli C, Cocco L, Liu JH, Jones AI, Yang J, Yang H, Thoms JAI, Unnikrishnan A, Pimanda JE, Pan R, Bassal MA, Voso MT, Tenen DG, Chai L. (2022) “Demethylation and Up-Regulation of an Oncogene after Hypomethylating Therapy.” New England Journal of Medicine, doi:10.1056/NEJMoa2119771

Link: https://www.nejm.org/doi/full/10.1056/NEJMoa2119771

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