Chromosomal abnormalities are found in 40% to 70% of patients who develop MDS, and they can occur in as many as 90% of patients with secondary MDS.  The most common chromosomal abnormalities are deletions of chromosomes 5, 7, 11, 12, 13, and 20, suggesting a role for tumor suppressor genes located on these chromosomes at the onset of this disease.
Around 80% of cases occur as a primary disease, but MDS can develop secondary to previous chemotherapy or radiation therapy.  The greatest risk is from long-term use of DNA alkylating agents, such as chlorambucil and cyclophosphamide, but prior therapy with other agents such as topoisomerase inhibitors and prior hematopoietic stem cell transplantation also increases risk of developing MDS.
Environmental risk factors may include exposures to mutagens such as tobacco and benzene.  Congenital risk factors include congenital neutropenia (Kostmann or Shwachman-Diamond syndrome) and Down syndrome (trisomy 21). DNA repair deficiency syndromes such as Fanconi anemia, ataxia telangiectasia, Bloom syndrome, xeroderma pigmentosum, and mutagen-detoxification (GSTq1-null), and history of aplastic anemia or paroxysmal nocturnal hemoglobinuria are also associated with increased risk of MDS.
It is believed that environmental exposures, hereditary factors, and gene alterations and deletions contribute to the development of a neoplastic multipotential hematopoietic stem cell clone. The stem cell clone gives rise to intermediate cell types that are defective and are particularly susceptible to apoptosis, resulting in death within the bone marrow before they reach maturity. There is increased activity in hematopoiesis, with cell division rates substantially higher than normal, but an inability for these cells to mature because of the inherent defect that has been introduced by the clone. Proliferation of the progenitor and early precursor cells is also increased and, as a result, these patients present with peripheral cytopenias despite a hypercellular marrow.  Another feature is dysregulation of the immune system, but whether this is a cause or an effect of the disease is unclear.