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Does Demethylation drugs cause cancer or treat cancer?
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NEJM: Does Demethylation drugs cause cancer or treat cancer?
The demethylating drugs decitabine and azacitidine are routine treatments for myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) by mechanisms that include irreversible binding and inhibition of DNA methyltransferases, leading to Demethylation and upregulation of tumor suppressor genes.
However, in patients with high-risk myelodysplastic syndromes or acute myeloid leukemia with low blast counts, overall survival is often shorter than expected based on clinical trials after demethylation therapy.
The researchers speculate that demethylating drugs can demethylate tumor suppressor genes and induce demethylation of oncogenes to up-regulate their expression.
On May 26, 2022, the New England Journal of Medicine (NEJM) published a research paper by Professor Chai Li and others from Brigham and Women’s Hospital affiliated to Harvard Medical School.
The study demonstrated in two small cohorts of myelodysplastic syndrome (MDS) patients that demethylating drugs designed to induce cell differentiation induced the expression of the oncogene SALL4 in 34% of patients , which was associated with poor prognosis.
The study also applied the site-specific demethylation technology CRISPR-DNMT1-interacting RNA (CRISPR-DiR) to demonstrate in cell lines and patients that demethylating drugs demethylate CpG regions in the 5′ untranslated region. Synthesis and up-regulation of SALL4 expression .
Myelodysplastic syndromes (MDS) originate from hematopoietic stem cells and are a class of malignant hematological diseases with high heterogeneity and easy transformation into acute myeloid leukemia (AML) .
Since the US FDA first approved demethylation drugs for the treatment of this disease in 2004, demethylation drugs have been widely used in cancer treatment.
Currently two demethylating drugs, 5-aza-2′-deoxycytidine (decitabine) and 5-azacytidine (azacitidine) , have been used clinically.
The researchers have proposed multiple mechanisms to explain how these drugs work, among which the idea that ” DNA methyltransferase activity is inhibited, which in turn leads to hypomethylation of tumor suppressor genes and up-regulation of tumor suppressor gene expression ,” is widely recognized.
In fact, demethylating drugs often act at the genome-wide level , and their global effects include not only demethylation of tumor suppressor genes and up-regulation of tumor suppressor gene expression, thereby exerting therapeutic effects, but also may include induction of oncogene demethylation sylation, which in turn leads to the up-regulation of oncogenes and has a pathogenic effect.
A long-standing unanswered question in the cancer field is whether these demethylating drugs to treat cancer also upregulate oncogene expression while activating tumor suppressor genes?
Another question is whether the up-regulation of these oncogenes could explain the poor clinical efficacy of demethylating drugs, and in the long run the controversial application of them?
On May 26, 2022, Professor Chai Li from Brigham and Women’s Hospital, affiliated to Harvard Medical School, published in the New England Journal of Medicine (NEJM) the title of “After Hypomethylation Therapy” Demethylation and Upregulation of Oncogenes” and gave definitive answers to these questions.
Oncogene SALL4 plays an important role in the occurrence of myelodysplastic syndromes, acute myeloid leukemia and various solid tumors, and its activation or abnormal expression in various cancers often corresponds to poor prognosis.
Mice overexpressing SALL4 were found to have a myelodysplastic-like phenotype, and activation of the Wnt-beta-catenin pathway led to their malignant transformation to leukemia.
The researchers speculate that demethylating drugs induce methylation erasure of oncogenes while demethylating tumor suppressor genes .
The research team selected the myelodysplastic syndrome group who used long-term demethylation drugs to carry out the study, and collected matched bone marrow samples from 68 patients before and after demethylation treatment.
After demethylation treatment, SALL4 expression was up-regulated in 34% of patients (23/68) and down -regulated in 66% of patients (45/68) , and it was striking that patients with up-regulated SALL4 expression corresponded to lower survival rate .
Changes of SALL4 expression in patients with myelodysplastic syndromes after treatment with demethylating drugs
Based on this phenomenon, we introduced site-specific demethylation in cell lines with low or no SALL4 expression, demonstrating a causal relationship between demethylation of key CpG regions of SALL4 and gene expression.
The researchers then directly demonstrated this key conclusion in drug-treated in vitro cells and in myelodysplastic syndrome patient samples before and after drug treatment, namely that ” demethylating drugs reduce CpG insula at key positions in the SALL4 gene.
Demethylation levels, thereby upregulating SALL4 expression ,” addressing a long-standing puzzling question for demethylating drugs.
The research logic clearly proves the potential “congenital deficiency” of demethylation drug therapy , that is, demethylating tumor suppressor genes will also up-regulate the expression of oncogenes, which not only treats the disease, but also has a very high pathogenicity.
Real-world data show that the efficacy of demethylating drugs in patients with myelodysplastic syndrome and acute myeloid leukemia is also far lower than clinical expectations.
Nearly 50% of patients do not respond to such drugs, and a small number of patients are demethylated.
The average survival time after drug treatment failure is less than 6 months, and the up-regulation of oncogene expression such as SALL4 may be an important reason, which shows that the applicable group of demethylation therapy is limited, and more targeted group therapy needs to be carried out in clinical practice;
The exact mechanism of the down-regulation of SALL4 expression in some patients after methylation drug treatment is still unclear, and extended research on this issue will contribute to the precise and efficient application of demethylation therapy in the future.
The research team is currently exploring whether the expression of SALL4 can be disrupted or reduced at the same time as demethylation therapy for effective treatment.
The response of oncogenes to demethylation therapy discovered in this study may be a phenomenon that cannot be ignored in epigenetic-related drug treatment.
Similar laws may exist in other cancers and oncogenes, and related models can also be used for demethylation in other cancers. therapeutic research.
In addition, demethylation drugs are like a double-edged sword, which upregulates tumor suppressor genes and also activates oncogenes.
It can be combined with other therapies to adjust the balance between oncogenes and tumor suppressor genes, and then play a role in disease treatment.
It can provide ideas for future research. Limited by the small sample size of this trial, future studies with larger sample sizes are needed to further verify this phenomenon and explore the underlying molecular mechanisms that different patients have different degrees of response to demethylation therapy.
NEJM: Does Demethylation drugs cause cancer or treat cancer?
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