Hypomethylating therapy may activate, upregulate oncogene
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Treatment with a hypomethylating agent may activate or upregulate SALL4, an oncogene that plays a key role in myelodysplastic syndrome and other cancers, according to study results published in The New England Journal of Medicine.
“Upregulation of SALL4 probably influences the clinical progression of the disease; similar biologic effects may accompany treatment with a hypomethylating agent in patients with cancers other than myelodysplastic syndrome,” Yao-Chung Liu, MD, of the department of pathology at Brigham and Women’s Hospital and division of hematology in the department of medicine at Taipei Veterans General Hospital in Taiwan, and colleagues wrote. “Although the upregulation of SALL4 may be associated with a worse prognosis, it may also provide an additional treatment option on the basis of SALL4-mediated cancer vulnerability.”
Rationale and methods
Liu and colleagues hypothesized that hypomethylating agents such as azacitidine and decitabine, which are used to treat blood cancers and solid tumors, not only contribute to tumor suppressor-gene demethylation but also may induce oncogene demethylation, according to study background. In the current study, they evaluated the potential of these agents to activate and upregulate SALL4, which has acted as an oncogene in experimental animal models of myelodysplastic syndrome and acute myeloid leukemia, they wrote.
The researchers used paired bone marrow samples taken before and after treatment with a hypomethylating agent from two cohorts of patients with myelodysplastic syndrome to study relationships of changes in SALL4 expression, response to treatment and clinical outcome.
Key findings
After treatment with hypomethylating agents, 40% of patients in cohort 1 (n = 10 of 25) and 30% of patients in cohort 2 (n = 13 of 43) had SALL4 upregulation, which correlated with a worse outcome. Using CRISPR-DNMT1-interacting RNA, a locus-specific demethylation technology, the researchers found demethylation of a CpG island within the 5 untranslated region that is crucial for SALL4 expression, they wrote.
“In cell lines and patients, we confirmed that treatment with a hypomethylating agent led to demethylation of the same CpG region and upregulation of SALL4 expression,” they added.
Implications
Further research is needed to completely understand the mechanisms of SALL4 upregulation after hypomethylating therapy, according to Liu and colleagues.
“We are currently exploring the concept that if SALL4 expression is upregulated, a concomitant targeted therapy that directly or indirectly mitigates SALL4 expression, function, or both could be added to the treatment plan,” they wrote.
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