Myelodysplastic Syndromes (MDS)



  • Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal stem cell disorders characterized by abnormal cellular maturation and peripheral blood cytopenias: anemia, thrombocytopenia, and/or neutropenia.
  • Dysplasia refers to an abnormality of development or differentiation in specific cell lines. In MDS, these changes take place in the bone marrow. MDS has similar pathological and cellular characteristics with acute myeloid leukemia (AML); however, MDS has a lower percentage of blast (<20%) in the peripheral blood and bone marrow. MDS has the ability to cause anemia, infections, bleeding, or transform into AML.



  • The incidence in the United States is approximately 4.9 cases per 100,000 population or 20,541 cases per year.
  • The incidence increases with age, with the majority occurring over the age of 80 years (incidence increases to 58 cases per 100,000 population per year).
  • More frequent in males and Caucasians

Etiology and Pathophysiology

  • MDS arises from mutations in hematopoietic blood cell lines due to various genetic and chromosomal abnormalities that occur de novo or due to environmental or iatrogenic exposure.
  • Environmental and iatrogenic exposures such as chemotherapy radiation; benzenes have been associated with the development of MDS.
  • Chemotherapeutic agents used for treatment of other malignancies, such as alkylators or topoisomerase II inhibitors, have been implicated as causes of MDS. MDS usually occurs 2 to 7 years after treatment.
  • Nongenetic mechanisms encompass apoptosis, pyroptosis, deregulated immunity, and inflammatory cytokine amplification (1).
  • Familial MDS is rare.
  • De novo MDS is not entirely understood but is thought to occur due to an oncogenic process resulting in one or more somatic mutations.
  • The classification of MDS by WHO (2016) is based on differences in morphology, dysplasia, and karyotype, particularly 5q deletion.
    • MDS with single lineage dysplasia
    • MDS with ring sideroblasts (MDS-RS)


  • Cytogenetic anomalies are observed in >90% of MDS patients, which include translocations or aneuploidy (loss or gain of a chromosome).
  • Individual cases generally have two to four mutations.
  • Deletion of the long arm of chromosome 5 (5q) is the most common abnormal karyotype and may be subdivided into two categories: treatment-related MDS with 5q deletion, usually with exposure to alkylating agents, versus de novo isolated 5q deletion. Patients with 5q deletion due to exposure to chemotherapeutic agents usually have other cytogenetic abnormalities and/or TP53 mutations. These tend to have a poorer prognosis. Isolated 5q deletion without other cytogenetic anomalies generally better prognosis. Other cytogenetic anomalies commonly studied include normal karyotype, deletion 7q (-7), trisomy 8 and -Y (2).
  • Mutated genes are involved in (2)
    • Epigenetic regulation: TET2, EZH2, IDH1, IDH2, DNMT3A, ASXL1
    • DNA repair: TP53
    • Transcriptional regulation: BCOR, ETV6, RUNX1
    • RNA splicing: U2AF35, ZRSR2, SF3B1, SRSF2
    • Cohesin complex: STAG2
    • Signal transduction: JAK2, CBL, NRAS
  • Mutations in the epigenetic modifiers: The concept is that any gain of function mutations in the DNA methyltransferases (DNMT3A and DNMT3B) leads to hypermethylation (a gene silencing mechanism that contributes to clonal evolution).
  • Changes in cytogenetics play a large role in the International Prognostic Scoring System (IPSS). Risk stratification and prediction of survival and transformation to AML.
    • IPSS very limited clinical and cytogenetic findings is based on outmoded diagnostic criteria, is not dynamic, and lacks the prognostic accuracy of subsequent models
    • IPSS-R incorporates clinical and pathologic features, but it does not include molecular findings.
    • IPSS-M was developed by the International Working Group for Prognosis in MDS (IWG-PM) using clinical, cytogenetic, and molecular data.

Risk Factors

  • Age: increased risk in patients >60 years old
  • Tobacco use
  • Chronic exposure to chemicals: benzene, pesticides, insecticides, and petroleum
  • Prior chemotherapy or radiation therapy
  • Inherited disorders: Fanconi anemia, Shwachman-Diamond syndromes, severe congenital neutropenia, and familial platelet disorder
  • An association has been noted in patients with end stage renal disease on dialysis (2).

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