Myelodysplastic syndrome (MDS) develops when stem cells in your bone marrow acquire genetic damage that prevents them from producing healthy blood cells. In most cases, this damage accumulates over a lifetime rather than arriving from a single event, which is why MDS is overwhelmingly diagnosed in people over 60. The causes range from acquired genetic mutations and chemical exposures to prior cancer treatment, and in a small number of cases, inherited genetic conditions.
How MDS Starts in the Bone Marrow
Your bone marrow contains stem cells that constantly divide and mature into red blood cells, white blood cells, and platelets. In MDS, one or more of these stem cells develops a mutation that gives it a growth advantage over normal cells. That mutant cell multiplies into a “clone,” gradually crowding out healthy blood production. The result is a marrow that’s often full of cells but can’t finish the job of making functional ones. Immature, abnormal cells build up, while the blood itself becomes deficient in one or more cell types.
More than 100 genes have been found to carry recurrent mutations in MDS. These mutations affect several critical cell functions: how DNA is read and interpreted, how genes are switched on or off, and how RNA is spliced together to build proteins. Chromosomal abnormalities, such as missing or extra chromosomes, appear in over 80% of patients. The most commonly mutated genes disrupt processes like DNA methylation (which controls gene silencing), RNA splicing (which assembles genetic instructions), and chromatin remodeling (which determines which genes are accessible).
Age and Clonal Hematopoiesis
Age is the single strongest risk factor for MDS. As you get older, your bone marrow stem cells naturally accumulate random mutations each time they divide. Most of these mutations are harmless. But occasionally one gives a stem cell a subtle survival advantage, allowing it to expand into a detectable clone. This phenomenon, called clonal hematopoiesis of indeterminate potential (CHIP), is common: studies detect it in roughly 10% of people over 70.
CHIP is not MDS. People with CHIP typically have normal blood counts and no symptoms. But it represents a precancerous state. Individuals with CHIP carry about a 12-fold higher risk of eventually being diagnosed with a blood cancer compared to people without detectable mutations. The actual rate of progression, however, is low: only about 0.5% to 1% per year, and most people with CHIP will never develop MDS or leukemia. The risk of progression appears proportional to the size of the mutant clone.
Prior Cancer Treatment
Therapy-related MDS accounts for a well-recognized subset of cases and is one of the few causes with a clear, identifiable trigger. Certain types of chemotherapy drugs damage the DNA of bone marrow stem cells, sometimes causing MDS years after the original cancer was treated.
Alkylating agents are the principal cause of therapy-related MDS. These drugs work by directly cross-linking DNA strands, which is effective against cancer but also harms normal stem cells. MDS from alkylating agents typically appears 5 to 10 years after exposure and often involves missing portions of chromosomes 5 and 7. A second class of drugs, topoisomerase II inhibitors, carries a faster timeline: MDS can develop within 1 to 3 years, usually with different chromosomal changes involving chromosome region 11q23. A third group, antimetabolites, has also been linked to treatment-related MDS.
Radiation therapy, whether for cancer treatment or from accidental exposure to ionizing radiation, has been extensively linked to blood cancers including MDS. The risk is higher when radiation is combined with chemotherapy.
Benzene and Chemical Exposures
Benzene is the most studied environmental cause of MDS. A large pooled analysis of petroleum workers found a clear dose-response relationship: workers with the highest cumulative benzene exposure had more than four times the risk of developing MDS compared to those with the lowest exposure. Workers who experienced peak exposures above 3 parts per million (even briefly, for 15 to 60 minutes weekly) had roughly six times the risk. Some data suggest increased risk may begin at exposures as low as 0.7 ppm.
Benzene is found in gasoline, industrial solvents, and cigarette smoke. People at highest risk include petroleum refinery workers, chemical plant employees, and those in rubber manufacturing or shoe-making industries where benzene-containing solvents were historically used.
Pesticides and Insecticides
A meta-analysis of 11 case-control studies covering nearly 2,000 MDS cases found that pesticide exposure roughly doubled the risk of developing MDS. When researchers broke the data down by pesticide type, the risk was specifically tied to insecticides, with a 71% increased risk. Herbicides and fungicides did not show a significant association. The link was strongest in studies from Europe and Asia.
Pesticides are thought to increase MDS risk through several mechanisms: promoting oxidative stress that damages DNA, causing chromosomal abnormalities, and disrupting cell signaling. Some pesticides can also bind to hormone receptors, altering gene expression in ways that may promote abnormal cell growth.
Smoking
Cigarette smoking is an established and modifiable risk factor for MDS. A meta-analysis found that people who have ever smoked are about 45% more likely to develop MDS than nonsmokers. Current smokers face an 81% increased risk, and former smokers carry a 67% increased risk, suggesting that quitting helps but doesn’t fully erase the accumulated damage.
The risk climbs with heavier use. Smoking 20 or more cigarettes per day raises MDS risk by 62%, and accumulating more than 20 pack-years of smoking nearly doubles it. Tobacco smoke contains benzene and dozens of other carcinogens that can directly damage bone marrow stem cell DNA.
Inherited Genetic Conditions
A small but important fraction of MDS cases, particularly those diagnosed in children and younger adults, arise from inherited genetic mutations passed down through families. The World Health Organization formally recognized “myeloid neoplasms with germline predisposition” as a diagnostic category in 2016, and the list of implicated genes has grown since.
GATA2 deficiency and SAMD9/SAMD9L syndromes are now recognized as the most frequent causes of primary childhood MDS. GATA2 deficiency is highly penetrant, meaning most people who carry the mutation will eventually develop problems, often progressing through immune deficiency before MDS emerges. SAMD9 mutations can cause a severe early-onset condition affecting multiple organ systems beyond the blood.
Other inherited syndromes that predispose to MDS include:
- Fanconi anemia: a DNA repair disorder with high MDS risk, with onset typically in the teens
- Shwachman-Diamond syndrome: variable MDS risk, with onset as early as age 5
- Severe congenital neutropenia: high MDS risk, often appearing in childhood or early adulthood
- Telomere biology disorders (dyskeratosis congenita): progressive bone marrow failure with MDS risk
- Down syndrome: increased susceptibility to myeloid neoplasms in early childhood
Germline mutations in RUNX1 carry a high risk of MDS with onset ranging from childhood to the late 70s (median around 33). DDX41 mutations tend to cause later-onset disease, with a median age around 55, making them particularly relevant for adults diagnosed with MDS who have a family history of blood cancers. If you’re diagnosed with MDS before age 50, or if multiple family members have had blood cancers, genetic testing for inherited predisposition may be appropriate.
When No Cause Is Found
For the majority of MDS cases, no single identifiable cause can be pinpointed. These are classified as “de novo” or primary MDS, and they likely result from the gradual accumulation of somatic mutations over decades of normal bone marrow activity. Each cell division carries a tiny chance of a copying error, and over 60, 70, or 80 years of life, enough errors can accumulate in the right combination of genes to trigger the disease. This is why MDS remains largely a disease of aging, even when no toxic exposure or inherited mutation is present.