Myelodysplastic Syndromes (MDS)



  • 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 transformation to acute myelogenous leukemia (AML).


The incidence in the United States is approximately 3 to 4 cases per 100,000 population per year, expanding to 35 cases per 100,000 population per year, for patients age >60 years.

>60,000 people with MDS resided in the country, which continues to increase as population ages

Etiology and Pathophysiology

  • MDS arises from mutations in hematopoietic blood cell lines.
  • 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 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-α (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.
      • 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 and 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
  • An association has been noted in patients with end stage renal disease on dialysis (4).

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 hematologic conditions such as paroxysmal nocturnal hemoglobinuria

There's more to see -- the rest of this topic is available only to subscribers.