Myelodysplastic Syndromes (MDS)

Myelodysplastic Syndromes (MDS) is a topic covered in the 5-Minute Clinical Consult.

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  • Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal stem cell disorders characterized by 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 and confer a tendency for leukemic transformation.


The incidence in the United States is approximately 3 to 4 cases per 100,000 population per year, expanding to 30 cases per 100,000 population per year, for patients age >70 years.

In 2012, >60,000 people with MDS resided in the country.

Etiology and Pathophysiology

  • MDS is clinically characterized by peripheral cytopenias, consequence of ineffective marrow hematopoiesis (premature cell death).
  • Nongenetic mechanisms encompass apoptosis, pyroptosis, deregulated immunity, and inflammatory cytokine amplification (see “Genetics” for genetic mechanisms) (1,2).
  • Low-risk MDS (LR-MDS) are characterized by deregulated immunity and apoptosis, whereas high-risk MDS (HR-MDS) are characterized by clonal expansion and transformation to acute myelogenous leukemia (AML).
  • A changing interplay of proapoptotic versus antiapoptotic signals is central in the progression of the disease.
  • In LR-MDS, stem cell programmed death occurs by different mechanisms: apoptosis, pyroptosis, and potentially autophagy.
    • Apoptosis: Tumor necrosis factor (TNF)-α, TNF-related apoptosis-inducing ligand (TRAIL), Fas ligand, and proapoptotic cytokines (TNF-α and IL-6) play a major role in stem cell apoptosis in LR-MDS.
    • Pyroptosis: It is an inflammatory cell death different from apoptosis that is considered sterile in nature.
      • Activation of nod-like receptors leads to formation of the inflammasome complex and caspase 1 activation that leads to pore formation in the plasma membrane of the cells; creates ionic gradients, water influx, cell swelling, and cell death (3)
      • This potentially also explains the morphologic changes seen in MDS (macrocytosis, enlarged cells).
  • Evolution to AML has been associated with upregulation of NFκB, enhanced activity of the Bcl2 and the inhibitors of apoptosis protein (IAP) families.
    • This is thought to be a mechanism of bypassing the apoptotic phenomenon in the bone marrow microenvironment.

  • Recurrent somatic mutations are observed in >90% of MDS patients.
  • Mutated genes are involved in:
    • 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).
  • It is unclear how these different molecular and genetic mechanisms translate into the same phenotypic manifestation of myelodysplasia and cytopenias.

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

General Prevention

Avoiding known cancer-causing industrial chemicals, such as benzene, and also tobacco, might lower the risk of developing MDS.

Commonly Associated Conditions

Myeloproliferative disorders and paroxysmal nocturnal hemoglobinuria

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