Agent Orange Exposure and Myelodysplastic Syndromes: Unraveling the Genetic Links and Implications for Veterans’ Health

More than five decades after the widespread use of Agent Orange during the Vietnam War, the long-term health effects of this herbicide remain a critical focus for clinicians, scientists, and the military veteran community. While Agent Orange has been definitively linked to a range of malignancies—including certain lymphomas and multiple myeloma—the association between Agent Orange and myelodysplastic syndromes (MDS) has only recently come to light. The fact that the link between Agent Orange-exposure and MDS was unclear, created real barriers for exposed veterans with MDS who were seeking care and disability benefits. [1][2]

Now, a new national study, recently published ahead of print in Blood Advances, provides compelling genetic evidence connecting Agent Orange exposure to MDS, a group of bone marrow cancers that often progress to acute myeloid leukemia(AML). In this article, we synthesize the latest findings, explore the genetic and epidemiological landscape of Agent Orange-associated MDS, and discuss the implications for diagnosis, treatment, and veterans’ benefits. [2]

Agent Orange: Historical Context and Toxicology
Agent Orange* was a phenoxy herbicide mixture used by the United States military as a strategic defoliant during the Vietnam War, intended to remove forest cover and destroy enemy crops. It was commonly diluted with kerosene, gasoline, or JP-4 jet fuel to facilitate aerial spraying. Importantly, Agent Orange was contaminated with dioxins—highly toxic organic pollutants with the potential to disrupt cellular processes and promote carcinogenesis. Approximately 2.6 million U.S. service members were potentially exposed to Agent Orange during their deployment.[3]

Dioxin exposure, even at low levels, is associated with increased risk for a variety of cancers, including prostate cancer, soft tissue sarcomas, non-Hodgkin lymphoma, and multiple myeloma. However, the link between Agent Orange and MDS, a less common group of hematologic malignancies, has been difficult to establish, in part due to the long latency between exposure and disease onset and the relative rarity of MDS in the general population.[2][3][4]

Myelodysplastic Syndromes
Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal hematopoietic disorders characterized by ineffective hematopoiesis, cytopenias, and an increased risk of progression to AML. While most cases arise without a clear antecedent (“de novo MDS”), a significant minority are linked to specific exposures—so-called “therapy-related MDS”—including cytotoxic chemotherapy, ionizing radiation, and certain organic solvents such as benzene.

The disease develops slowly over a lifetime, accumulating genetic mutations. MDS affects up to 20,000 Americans each year, typically those older than 70 years of age. Some aggressive cases of MDS eventually progress to acute myeloid leukemia.

“MDS isn’t a one-hit wonder,” Mikkael Sekeres, M.D., chief and professor of hematology at Sylvester Comprehensive Cancer Center, part of the University of Miami Miller School of Medicine, said.

“Patients have one genetic mutation that occurs, then another, then another. It takes decades for those mutations to develop, and with an exposure like AO, patients can acquire that first mutation at a younger age than they normally would,” he further noted.

The potential for Agent Orange and dioxins to act as hematopoietic toxins has long been hypothesized. Epidemiological evidence from other genotoxic exposures, such as atomic bomb survivors in Japan, shows that increased risk for MDS can persist for decades after exposure. However, the rarity of MDS and the challenge of long-term follow-up have limited definitive studies in Agent Orange-exposed populations.

A New National Study: Genetic Insights into Agent Orange-Associated MDS
The recently published study in Blood Advances represents a landmark effort to characterize the genetic underpinnings of MDS in Agent Orange-exposed veterans. Led by Sekeres, the research builds on earlier findings presented at the 2025 American Society of Hematology (ASH) Annual Meeting, which first noted an association between Agent Orange exposure and increased risk of MDS.

Drawing on data from the National Heart, Lung, and Blood Institute’s MDS Natural History Study—a prospective national registry—the investigators analyzed 2,115 patients, of whom 130 (6.1%) reported Agent Orange-exposure. Notably, 96% of those exposed were men, and more than half (54%) of AO-exposed individuals developed MDS or a related precursor, compared to just 37% in the unexposed group.

“This study has been a personal quest,” Sekeres said. “I see veterans who develop these conditions and need expensive medical care, but I can’t write a letter that establishes causality because, before this study, we hadn’t clearly linked Agent Orange to MDS,” he added.

Key Clinical Findings:

• Earlier Onset: Agent Orange-exposed veterans were diagnosed with MDS several years earlier, on average, than unexposed patients.
• Increased Aggressiveness: During the first two years after diagnosis, Agent Orange-exposed patients were about 80% more likely to experience disease progression, including transformation to more severe MDS or AML.
• Overall Survival: Despite these indicators of more aggressive disease, overall survival rates were similar between AO-exposed and unexposed patients within the study period.

Genetic and Cytogenetic Landscape of Agent Orange-Associated MDS
One of the most significant contributions of this study is the detailed genetic analysis of MDS cases in Agent Orange-exposed veterans. By leveraging next-generation exome sequencing, the researchers sought to identify somatic mutations and cytogenetic abnormalities that might differentiate Agent Orange-associated MDS from de novo or therapy-related cases. The study outcomes showed:

• High-Risk Chromosomal Abnormalities: Agent Orange-exposed patients with MDS were more than twice as likely to harbor high-risk chromosomal changes, suggesting a predisposition to more aggressive disease biology.
• Mutation Spectrum: Specific mutations—including TET2, SRSF2, U2AF1, ZRSR2, and KRAS—were found at higher frequencies in the Agent Orange group. These genes are crucial for proper RNA splicing and protein synthesis in bone marrow cells; when mutated, they can contribute to malignant transformation.
• Driver Mutation Similarity: Overall, the pattern of driver mutations in AO-associated MDS was similar to that observed in de novo MDS, with a predominance of mutations in genes involved in RNA splicing (SF3B1, U2AF1, SRSF2) and epigenetic regulation (TET2, DNMT3A, ASXL1).
• DNA Damage Pathways: Contrary to what might be expected from a genotoxic exposure, the study did not find an enrichment of mutations in classic DNA damage response genes (e.g., TP53, PPM1D), which are more commonly mutated in therapy-related MDS. This suggests that Agent Orange may promote MDS through mechanisms other than direct DNA damage—possibly by promoting the selection and clonal expansion of mutant hematopoietic stem cells.

Further analysis of mutational signatures revealed that most mutations were consistent with age-related cytidine deamination, leading to C to T transitions within CpG dinucleotides. This finding indicates that the mutational landscape of Agent Orange-associated MDS closely mirrors that of age-related, de novo cases, rather than that of MDS driven by direct mutagenic exposures.

Epidemiological Patterns and Health Disparities
The study also uncovered important epidemiological patterns among Agent Orange-exposed veterans. Strikingly, Black men were overrepresented among those reporting Agent Orange exposure—comprising about 20% of the Agent Orange-exposed male cohort, more than double their proportion in the unexposed group. Even after adjusting for other variables, Black veterans were nearly three times as likely to report Agent Orange exposure.

This disparity raises questions about differential exposure risks during military service. While the study was not designed to determine causality, the findings suggest that Black service members may have been more likely to be placed in roles or geographic areas with higher Agent Orange exposure, reflecting broader patterns of occupational and environmental injustice.

Clinical and Policy Implications
For veterans living with MDS, the identification of a unique genetic and clinical profile associated with Agent Orange exposure carries significant practical implications. First, the recognition that Agent Orange-exposed individuals are at increased risk for earlier-onset, more aggressive MDS should inform clinical surveillance and management strategies. In particular, the higher likelihood of disease progression to AML underscores the need for vigilant follow-up and consideration of early intervention or enrollment in clinical trials.

Second, the new genetic data strengthen the case for policy change. Currently, the U.S. Department of Veterans Affairs (VA) does not uniformly classify MDS as a presumptive Agent Orange-related condition, meaning that veterans must often provide extensive documentation to establish a service connection for benefits—typically requiring a strong nexus letter from a clinician. The findings from this study provide the strongest evidence to date that Agent Orange exposure is a risk factor for aggressive MDS, and they support the inclusion of MDS in the list of Agent Orange presumptive conditions.

Following the presentation of these results at the ASH meeting, Sekeres received numerous inquiries from veterans seeking to understand whether their diagnosis could finally be acknowledged as service-connected. For many, this research represents a vital step toward accessing the care and benefits they deserve.

Limitations and Future Research Directions
While this study represents a significant advance, several limitations must be acknowledged. The relative rarity of MDS and the long latency between Agent Orange exposure and disease development make large-scale epidemiological studies challenging. The genetic cohort analyzed was modest in size, and while the mutational spectrum did not differ dramatically from de novo MDS, subtle differences or rare mutational events may have been missed.

Additionally, the absence of a unique mutational signature does not exclude the possibility that Agent Orange acts through non-genotoxic mechanisms—such as altering the bone marrow microenvironment or promoting the clonal expansion of pre-existing mutant stem cells. Longitudinal studies of Agent Orange-exposed veterans, particularly those conducted closer in time to exposure, may yield further insights into the evolving clonal architecture of MDS.

Finally, the overrepresentation of Black veterans among Agent Orange-exposed individuals highlights a need for further investigation into the social and environmental determinants of exposure and disease risk, warranting a broader approach to veterans’ health research.

Watershed moment
The new genetic and clinical data linking Agent Orange exposure to myelodysplastic syndromes mark a watershed moment in veterans’ health research. More than 50 years after their service, Vietnam veterans are now better able to understand the biological underpinnings of their disease—and, crucially, to advocate for recognition and care. The findings also advance our scientific understanding of environmental carcinogenesis, demonstrating that Agent Orange exposure increases the risk of developing MDS with a predilection for aggressive chromosomal changes and earlier onset, even in the absence of a classic mutational signature.

As the field moves forward, further epidemiological and molecular studies are essential to refine risk estimates, clarify mechanisms, and guide clinical management. For clinicians, researchers, and policymakers alike, this work underscores the imperative to address the enduring legacy of military toxic exposures and to ensure equitable care and support for all veterans.

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Note:* Agent Orange, the main chemical herbicide mixture sprayed, included a 50:50 mixture of 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T). At the time of the spraying, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most toxic form of dioxin, was an unintended contaminant generated during the production of 2,4,5-T and was, therefore, present in Agent Orange and some other formulations sprayed in Vietnam. [3]

Reference
[1] Sperling AS, Leventhal M, Gibson CJ, Ebert BL, Steensma DP. Myelodysplastic syndromes (MDS) occurring in Agent Orange exposed individuals carry a mutational spectrum similar to that of de novo MDS. Leuk Lymphoma. 2020 Mar;61(3):728-731. doi: 10.1080/10428194.2019.1689394. Epub 2019 Nov 12. PMID: 31714164; PMCID: PMC7268906.
[2] Sekeres MA, DeZern AE, Otterstatter M, Padron E, Al Baghdadi T, Foran JM, Komrokji RS, Abel GA, Saber W, Gore SD, Lee C, Bejar R, Liu JJ, Deeg HJ, Sherman S, Lindsley RC, Walter MJ, Gillis N. Exposure to Agent Orange and Association with Myelodysplastic Syndromes. Blood Adv. 2026 Feb 24:bloodadvances.2025019262. doi: 10.1182/bloodadvances.2025019262. Epub ahead of print. PMID: 41734386.
[3] National Academies of Sciences, Engineering, and Medicine; Health and Medicine Division; Board on Population Health and Public Health Practice; Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides (Eleventh Biennial Update). Veterans and Agent Orange: Update 11 (2018). Washington (DC): National Academies Press (US); 2018 Nov 15. PMID: 30629395.
[4] Chamie K, DeVere White RW, Lee D, Ok JH, Ellison LM. Agent Orange exposure, Vietnam War veterans, and the risk of prostate cancer. Cancer. 2008 Nov 1;113(9):2464-70. doi: 10.1002/cncr.23695. PMID: 18666213.

Featured image: During the Pink Rose test program in 1967 target areas near Tay Ninh and An Loc, Vietnam, were sprayed with Agent Orange. National Archives and Records Administration (NARA) – 542337. Photo Public Domain.

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