A A new study published in Development of Blood provides the clearest evidence yet that exposure to Agent Orange—a chemical agent widely used during the Vietnam War—may leave permanent genetic defects that increase the risk of myelodysplastic syndromes (MDS), a group of bone cancers that can progress to acute leukemia.
Led by Mikkael Sekeres, MD, director and professor of hematology at the Sylvester Comprehensive Cancer Center, part of the University of Miami Miller School of Medicine, the research builds on findings presented before the Annual Meeting of the American Society of Hematology 2025. The study supports the growing understanding of how environmental toxins contribute to cancer genomically.
The long-suspected connection is coming into focus
MDS is a complex blood disorder characterized by impaired production of blood cells, low blood counts (cytopenias), and a high risk of transformation to acute myeloid leukemia. Although aging and genetic changes play a role, environmental exposures have long been suspected as contributing factors.
Agent Orange, a phenoxy herbicide contaminated with carcinogenic dioxins, has been linked to several types of cancer—including prostate cancer and lymphoid malignancies—but until now, a firm link to MDS has been elusive. “This is the first study to show a link between orange exposure and the development of MDS,” Sekeres said, emphasizing the importance of research to establish a biological and medical connection.
This study is based on the National Natural History Study of MDS, sponsored by the National Heart, Lung, and Blood Institute. This large, prospective cohort followed 2,100 patients across 161 locations in the United States between 2016 and 2024. “Our work looked at people who had anemia and entered a clinical trial that was supported through the NHLBI in which we were trying to find patients who eventually had myeloid dysplastic syndrome,” a cancer similar to cancer, “Sekeres syndrome”
During the eight years of enrollment, about half of the participants were eventually diagnosed with MDS or related conditions such as clonal cytopenia of unknown significance (CCUS), while the other half were not. He said: “We enrolled patients over a period of eight years, more than 2100 patients and about half of them developed MDS or an earlier stage, and about half did not. “It represented a perfect group to study the effects of exposure to, in this case, Agent Orange.”
Participants filled out detailed questionnaires about environmental exposures, including Agent Orange. “We gave a questionnaire to prospective patients about their exposure to Agent Orange,” Sekeres noted.
Studies show that people exposed to Agent Orange are more likely to have MDS or related conditions before compared to people not exposed. Moreover, the disease behaved aggressively. “We found that exposure to Agent Orange was associated with eventually developing or having a greater likelihood of developing myeloid dysplastic syndrome or early conditions,” Sekeres said.
Even more surprising was the effect on disease progression. He added: “We also found that there is a possibility of being associated with increased disease progression.” Once a person is diagnosed with a certain disorder, it is likely to develop into MDS. If he had low-risk MDS, he could have turned into high-risk MDS, and if he had had high-risk MDS, he could have turned into leukemia.”
This is consistent with the clinical hypothesis that environmental pathogens can accelerate the accumulation of genetic damage over time. “Now it is not surprising when we think that we have found a relationship between exposure to a large agent and having complex genetic changes,” he said.
Genetic fingerprints of exposure
The main contribution of the study is its use of next-generation sequencing to identify mutations in 60 genes that are often associated with MDS. This allowed researchers to go beyond epidemiology and into the molecular cause. “When we did this research, we looked to see if Agent Orange was associated with certain genetic changes in patients with MDS or early stages, and it was found,” Sekeres said.
Patients exposed to Agent Orange did not show completely specific changes—but they did show high frequencies of certain harmful changes. “We screened patients for the 60 most common mutations associated with myelodysplastic syndrome using next-generation sequencing among those 60 mutations,” he explained.
Among the notable findings, TET2 Changes occurred in 26% of exposed patients compared to 17% of unexposed patients. SRSF2 mutations in genes, involved in RNA splicing, almost doubled, occurring in 14% of exposed patients compared to 8% of unexposed patients. U2AF1 Changes were seen in 9% of exposed patients compared to 5% of unexposed patients, while ZRSR2 changes occurred in 5% versus 2%, respectively. KRAS Changes were also more frequent among exposed patients, occurring in 3% compared with 1% of unexposed patients.
Agent Orange dioxin contamination is known to disrupt DNA repair mechanisms and alter epigenetic regulation, potentially accelerating the accumulation of mutations over decades. Studies mirror findings in other exposed populations, such as atomic bomb survivors, where early life exposure leads to complex genetic abnormalities later in life. “Patients tended to have more changes and worse changes and found specific relationships between orange exposure and certain genetic mutations or genetic mutations,” Sekeres said.
In addition to establishing a cause, the study opens new doors for precision medicine—planning diagnosis and treatment based on exposure history and genetic risk. According to Sekeres, there are few ways this data can be used.
First, if someone served in Vietnam and was exposed to Agent Orange and started to have anemia, Sekeres said, “we would definitely recommend that person seek care from a hematologist and maybe go for a bone marrow test to make sure they don’t have MDS or an early stage.”
Second, doctors should recognize the high risk of development. “If diagnosed with MDS, the patient and their doctor should be aware that MDS may progress to something more aggressive,” he said.
The third, and perhaps the most promising, is the therapeutic effect. “There are certain pathways that may be more affected. So when targeted drugs are being developed, that may provide an opportunity to treat these patients,” Sekeres explained.
For example, mutations in RNA splicing genes suggest potential for spliceosome-targeting therapies—an area of ongoing drug development. “There have been attempts to develop, for example, an inhibitor of the spliceosome. Unfortunately it was a false study, but you can imagine that if someone has a pre-existing condition of the orange body… TET2,” he said.
Such methods can change the treatment before the time of this disease, which is an opportunity to prevent the development of leukemia.
A first step in environmental oncology
Sekeres sees the work as the start of broader research into how environmental exposures affect cancer genetics across diseases. “This could be the basis for identifying the changes associated with exposure to Agent Orange and to see if patients with other similar diseases have similar patterns of change,” he said.
The findings also have major implications for US veterans, many of whom have struggled to receive MDS care due to the lack of a known link to exposure to Agent Orange. “One of the reasons why I wanted to do this study… is because I was looking after people who served in Vietnam, who were exposed to Agent Orange and who developed MDS, but they couldn’t connect to services,” said Sekeres.
Without formal approval, important diagnostic tools such as genomic sequencing may not be covered by the Veterans Administration. “My hope is that this study now creates a link … that will prompt the administration to finally make MDS a disease related to Agent Orange exposure and get these veterans to receive health care … including organizing them,” he said.
The study represents a breakthrough in understanding how environmental exposures leave lasting molecular scars that cause cancer risk decades later. By linking exposure to Agent Orange not only to increased rates of MDS but also to genetic variants and aggressive disease pathways, research bridges epidemiology, genomics and clinical care.
For patients, doctors and policy makers, it provides a clearer map: identify those at risk earlier, monitor them more closely, and develop targeted therapies that address specific changes in the disease. In the era of precision medicine, such information is important – not only for treating cancer but also for understanding its origin.
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