[12] Some people have a history of exposure to chemotherapy (especially alkylating agents such as melphalan, cyclophosphamide, busulfan, and chlorambucil) or radiation (therapeutic or accidental), or both (e.g., at the time of stem cell transplantation for another disease).

[13] A link may exist between the development of MDS "in atomic-bomb survivors 40 to 60 years after radiation exposure" (in this case, referring to people who were in close proximity to the dropping of the atomic bombs in Hiroshima and Nagasaki during World War II).

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.

MDS after exposure to DNA topoisomerase II inhibitors occurs after a shorter latency of only 1–3 years and can have a 11q23 translocation.

[15] 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.

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.

[19] 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.

[20] 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.

[21] 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.

[27] Mutations in the genes encoding for isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) occur in 10–20% of patients with myelodysplastic syndrome,[28] and confer a worsened prognosis in low-risk MDS.

The GATA2 protein is a transcription factor critical for the embryonic development, maintenance, and functionality of blood-forming, lymph-forming, and other tissue-forming stem cells.

In consequence of these mutations, cellular levels of GATA2 are low and individuals develop over time hematological, immunological, lymphatic, or other presentations.

[36] A typical diagnostic investigation includes: The features generally used to define an MDS are blood cytopenias, ineffective hematopoiesis, dyserythropoiesis, dysgranulopoiesis, dysmegakaropoiesis, and increased myeloblasts.

The best way to diagnose dysplasia is by morphology and special stains (PAS) used on the bone marrow aspirate and peripheral blood smear.

Dysplasia in the myeloid series is defined by: On the bone-marrow biopsy, high-grade dysplasia (RAEB-I and RAEB-II) may show atypical localization of immature precursors, which are islands of immature precursors cells (myeloblasts and promyelocytes) localized to the center of the intertrabecular space rather than adjacent to the trabeculae or surrounding arterioles.

[citation needed] In the late 1990s, a group of pathologists and clinicians working under the World Health Organization (WHO) modified this classification, introducing several new disease categories and eliminating others.

In 2008, 2016, and 2022, the WHO developed new classification schemes that incorporated genetic findings (5q-) alongside morphology of the cells in the peripheral blood and bone marrow.

(Increased Blasts) MDS may present with isolated neutropenia or thrombocytopenia without anemia and with dysplastic changes confined to the single lineage.

[11] Most cases of unclassifiable MDS from the 2008 WHO version would be considered Clonal Cytopenias of Undetermined Significance (CCUS) by the WHO 5th ed.

[11] Another subtype called Myeloid neoplasms with germ line predisposition and organ dysfunction includes CEBPA/DDX41/RUNX1 disorders, GATA2 deficiency and SAMD9/9L syndromes.

[30] The hypomethylating agent decitabine has shown a similar survival benefit to azacitidine and has a response rate as high as 43%.

[49] Lenalidomide is effective in reducing red blood cell transfusion requirement in patients with the chromosome 5q deletion subtype (5q- syndrome) of MDS and the median duration of response is greater than 2 years.

[51][36][52] HLA-matched allogeneic stem cell transplantation, particularly in younger (i.e. less than 40 years of age) and more severely affected patients, offers the potential for curative therapy.

A third chelating agent is available, deferiprone, but it has limited utility in MDS patients because of a major side effect of neutropenia.

Iron overload not only leads to organ damage, but also induces genomic instability and modifies the hematopoietic niche, favoring progression to acute leukemia.

[55] Indicators of a good prognosis: Younger age; normal or moderately reduced neutrophil or platelet counts; low blast counts in the bone marrow (< 20%) and no blasts in the blood; no Auer rods; ringed sideroblasts; normal or mixed karyotypes without complex chromosome abnormalities; and in vitro marrow culture with a nonleukemic growth pattern Indicators of a poor prognosis: Advanced age; severe neutropenia or thrombocytopenia; high blast count in the bone marrow (20–29%) or blasts in the blood; Auer rods; absence of ringed sideroblasts; abnormal localization or immature granulocyte precursors in bone marrow section; completely or mostly abnormal karyotypes, or complex marrow chromosome abnormalities and in vitro bone marrow culture with a leukemic growth pattern Karyotype prognostic factors: Cytogenetic abnormalities can be detected by conventional cytogenetics, a FISH panel for MDS, or virtual karyotype.

The best prognosis is seen with RA and RARS, where some nontransplant patients live more than a decade (typical is on the order of three to five years, although long-term remission is possible if a bone-marrow transplant is successful).

[citation needed] Since the early 20th century, some people with acute myelogenous leukemia were begun to be recognized to have a preceding period of anemia and abnormal blood cell production.