MDS most often develops without an identifiable cause. Risk factors include exposure to an agent known to cause DNA damage, such as
radiation, benzene, and certain chemotherapies; other risk factors have been inconsistently reported. Proving a connection between a suspected exposure and the development of MDS can be difficult, but the presence of genetic abnormalities may provide some supportive information. Secondary MDS can occur as a late
toxicity of cancer therapy (therapy-associated MDS, t-MDS). MDS after exposure to radiation or
alkylating agents such as busulfan,
nitrosourea, or
procarbazine, typically occurs 3–7 years after exposure and frequently demonstrates loss of chromosome 5 or 7. MDS after exposure to
DNA topoisomerase II inhibitors occurs after a shorter latency of only 1–3 years and can have an 11q23 translocation. Other pre-existing bone-marrow disorders, such as
acquired aplastic anemia following immunosuppressive treatment and
Fanconi anemia, can evolve into MDS. MDS is thought to arise from
mutations in the
multipotent bone-marrow stem cell, but the specific defects responsible for these diseases remain poorly understood.
Differentiation of blood precursor cells is impaired, and a significant increase in levels of
apoptotic cell death occurs in bone-marrow cells. Clonal expansion of the abnormal cells results in the production of cells that have lost the ability to differentiate. If the overall percentage of bone-marrow
myeloblasts rises over a particular cutoff (20% for
WHO and 30% for
FAB), then transformation to
acute myelogenous leukemia (AML) is said to have occurred. The progression of MDS to AML is a good example of the
multistep theory of carcinogenesis in which a series of mutations occurs in an initially normal cell and transforms it into a
cancer cell. Although recognition of leukemic transformation was historically important (see
History), a significant proportion of the
morbidity and
mortality attributable to MDS results not from transformation to AML, but rather from the cytopenias seen in all MDS patients. While anemia is the most common
cytopenia in MDS patients, given the ready availability of
blood transfusion, MDS patients rarely experience injury from severe anemia. The two most serious complications in MDS patients resulting from their cytopenias are bleeding (due to lack of platelets) or infection (due to lack of white blood cells). Long-term transfusion of packed red blood cells leads to
iron overload.
Genetics The recognition of
epigenetic changes in
DNA structure in MDS has explained the success of two (namely the hypomethylating agents
5-azacytidine and
decitabine) of three (the third is
lenalidomide) commercially available medications approved by the
U.S. Food and Drug Administration to treat MDS. Proper
DNA methylation is critical in the regulation of proliferation genes, and the loss of DNA methylation control can lead to uncontrolled cell growth and cytopenias. The recently approved
DNA methyltransferase inhibitors take advantage of this mechanism by creating a more orderly DNA methylation profile in the
hematopoietic stem cell nucleus, thereby restoring normal blood counts and retarding the progression of MDS to
acute leukemia. Some authors have proposed that the loss of
mitochondrial function over time leads to the accumulation of DNA mutations in hematopoietic stem cells, and this accounts for the increased incidence of MDS in older patients. Researchers point to the accumulation of mitochondrial
iron deposits in the
ringed sideroblast as evidence of mitochondrial dysfunction in MDS.
DNA damage Hematopoietic stem cell aging is thought to be associated with the accrual of multiple genetic and
epigenetic aberrations leading to the suggestion that MDS is, in part, related to an inability to adequately cope with
DNA damage. An emerging perspective is that the underlying mechanism of MDS could be a defect in one or more pathways that are involved in
repairing damaged DNA. In MDS an increased frequency of
chromosomal breaks indicates defects in DNA repair processes. Also, elevated levels of
8-oxoguanine were found in the DNA of a significant proportion of MDS patients, indicating that the
base excision repair pathway that is involved in handling oxidative DNA damages may be defective in these cases. By 2005,
lenalidomide, a
chemotherapy drug, was recognized to be effective in MDS patients with the
5q- syndrome, and in December 2005, the US FDA approved the drug for this indication. Patients with isolated 5q-, low
IPSS risk, and transfusion dependence respond best to lenalidomide. Typically, the prognosis for these patients is favorable, with a 63-month median survival. Lenalidomide has dual action, by lowering the malignant clone number in patients with 5q-, and by inducing better differentiation of healthy erythroid cells, as seen in patients without 5q deletion.
Splicing factor mutations Mutations in splicing factors have been found in 40–80% of people with MDS, with a higher incidence of mutations detected in people who have more
ring sideroblasts.
IDH1 and IDH2 mutations Mutations in the genes encoding for
isocitrate dehydrogenase 1 and 2 (
IDH1 and
IDH2) occur in 10–20% of patients with myelodysplastic syndrome, and confer a worsened prognosis in low-risk MDS. Because the incidence of
IDH1/2 mutations increases as the disease malignancy increases, these findings together suggest that
IDH1/2 mutations are important drivers of progression of MDS to a more malignant disease state.
Transient myeloproliferative disease Transient myeloproliferative disease, renamed Transient Abnormal Myelopoiesis (TAM), is the abnormal proliferation of a
clone of noncancerous
megakaryoblasts in the liver and bone marrow. The disease is restricted to individuals with Down syndrome or genetic changes similar to those in Down syndrome, develops during pregnancy or shortly after birth, and resolves within 3 months, or in about 10% of cases, progresses to
acute megakaryoblastic leukemia. == Diagnosis ==