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Pathogenesis of MDS: An overview of molecular and non-molecular aspects of the disease

PubMed Abstract: 
Original Publication Date: 
Tuesday, May 12, 2015

Research Review:

The myelodysplastic syndromes (MDS) are a bone marrow failure disorder characterized by ineffective maturation of cells, low blood counts, and risk of transformation to acute myeloid leukemia (AML).  The average age of onset is late 60s to early 70s.  There are currently three FDA-approved medications for MDS: lenalidomide, azacitidine, and decitabine.  Although these agents can be effective in the treatment of MDS, none are curative.  The only potential curative therapy is a stem cell transplant.  It is known that genetic/chromosomal instability can contribute to development of the disease and affect prognosis.  Researchers are using high throughput genetic technologies and next generation sequencing technologies in an effort to understand why patients get MDS. 


  • Genetic defects are common in MDS, including cytogenetic abnormalities, gene mutations, and abnormal gene expression.  Many of these abnormalities are present at diagnosis although they can also develop during the disease course and are often associated with worsening disease.
  • Cytogenetic abnormalities are found in approximately 50% of primary MDS and 80% of secondary MDS, which develops in the setting of prior chemotherapy or radiation.  Complex cytogenetics (3 or more abnormalities) is associated with a worse prognosis.
  • Somatic mutations in stem cells are thought to contribute to the development of MDS although no specific defect has been clearly identified.  It is estimated that 78% of MDS patients carry at least one somatic mutation.  Knowledge of these mutations may help in diagnosing patients as well as assessing prognosis and treatment response.  Certain mutations, for example, are associated with a worse overall survival, including TP53, EZH2, ETV6, RUNX1, and ASXL1.
  • Newer technologies such as high throughput whole genome scanning technologies and next generation sequencing, have helped us in our understanding of the mutations involved in the pathogenesis of MDS.  Understanding the molecular basis of these genes will ultimately guide physicians in choosing targeted therapies for individual patients.
  • Conventional cytogenetic methods cannot always detect chromosomal abnormalities in MDS patients. New methods, such as SNP-A karyotyping, are more sensitive.  SNP-A technology can detect lesions in 50% of patients who have a normal cytogenetic profile. 
  • One of the main pathways that are altered in patients with MDS is epigenetic regulation, which involves DNA methylation and histone modification.  DNMT3A, TET2, IDH1/2, ASXL1, EZH2, and UTX are some of the genes involved in this pathway.  Detecting mutations such as DNMT3A and TET2 can be important since patients with these mutations tend to have better responses to hypomethylating agents, such as azacitidine and decitabine.
  • Splicing factor genes are mutated in about 50% of MDS patients and include mutations in the genes SF3B1, U2AF1, SRSF2, ZRSR2, and PRPF8.  SF3B1 mutations are more common in lower-risk MDS and are associated with a favorable prognosis.  U2AF1 and SRSF2 are associated with higher-risk MDS.  Spliceosome inhibitors have been proposed as a method to target the mutations associated with this pathway. 
  • Signaling pathway mutations include JAK2 and CBL.  JAK2 mutations are more common in myeloproliferative neoplasms. 
  • Another pathway that is dysregulated in MDS is transcription of genes and cell cycle progression/apoptosis, and genes involved in this pathway include RUNX1, TP53, and BCOR/BCORLI.  These mutations are often associated with worse prognosis in MDS patients. 
  • It is likely that there are also non-genetic mechanisms involved in the development of MDS, including factors associated with the bone marrow microenvironment, apoptosis, cytokines, telomere length, and immune factors. 


MDS is a heterogeneous disease with many factors contributing to its development.  Molecular mutations in several pathways have been associated with the disease, which may help to develop new targets and therapies for patients.

Reviewer Bio: 
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