Study: Blood Disorder Treatment May Activate Cancer-Causing Gene in Some Patients

Multinational study confirms unintended consequence of demethylating drugs

A team led by researchers from Taiwan found that demethylating drugs for a group of blood cancers may upregulate the SALL4 oncogene. This photo shows human blood samples on an automated testing line. David Silverman/Getty Images

The current treatment for a group of blood cancers called myelodysplastic syndromes (MDS) involves demethylating drugs that inhibit the growth of cancer cells. However, a multinational team led by researchers from Taiwan, Singapore, and the United States has found that the drugs may actually activate a known oncogene—a gene that under certain conditions can cause cancer. Activating the “sleeping” oncogene may lead to poor survival rates.

In a press release on Oct. 20, Taiwan’s Taipei Veterans General Hospital (NCGH) discussed the discovery, which may change current thinking on the treatment of MDS and other cancers.

MDS affects hematopoiesis, the process whereby the bone marrow produces blood cells and platelets. MDS patients may have myeloblasts—early forms of blood cells normally found only in bone marrow—in their blood. About 30 percent of MDS patients progress to acute myeloid leukemia.

The current treatment of patients with MDS relies mainly on hypomethylating agents (HMAs) to inhibit the growth of cancerous cells. These drugs work by inhibiting methylation, a biochemical process responsible for a host of functions in the body. Dysregulation of DNA methylation can encourage gene mutation, contributing to cancer.

Two HMAs, azacitidine and decitabine, are currently FDA-approved for use in MDS patients.

In collaboration with research teams from top universities in Singapore, Italy, China, and the United States, Dr. Yao-Chung Liu, of the Department of Hematology at Taipai Veteran’s General Hospital, studied a group of 68 patients treated with HMAs.

The scientists found that while HMA therapy is an effective therapy in many patients with MDS, in a significant subset of patients the therapy can induce the body to activate the SALL4 oncogene, leading to further deterioration.

The SALL4 oncogene plays an important role in MDS and other cancers. It is found not only in bone marrow, but also in cancerous tissues of the liver, stomach, intestines, and breast.

Researchers found that the SALL4 oncogene was activated in 30 percent to 40 percent of the patients studied and was associated with a worse outcome.

Researchers further compared the difference in mortality risk between the high and low expressions of the SALL4 oncogene. The results showed that the risk of death was 3 to 6 times higher in those with higher SALL4 expression than in those with lower expression, and that the risk of death increased over time.

The study confirmed that the use of demethylating drugs in patients with diagnosed MDS, while suppressing tumor growth, has a tendency to upregulate the SALL4 oncogene, reducing the overall survival rate in patients.

The new findings disprove previous assumptions that the drug only inhibits the growth of cancerous cells.

The results of the study were published in the May issue of the New England Journal of Medicine and have generated widespread attention.

Hypomethylating agents are a “blessing and a curse,” say authors Juliane Grimm and Mascha Binder in an August article in the journal Signal Transduction and Targeted Therapy.

In an Oct. 28 article on the website of the Harvard Stem Cell Institute, author Alice McCarthy says the discovery may lead to more effective treatment for MDS patients: it “raises the possibility that early treatment with anti-SALL4 pathway agents could influence the outcomes of HMA-treated patients.”