The Genetic Basis and Expanding Role of Molecular Analysis in the Diagnosis, Prognosis, and Therapeutic Design for Myelodysplastic Syndromes  Grant E. Nybakken, Adam Bagg  The Journal of Molecular Diagnostics  Volume 16, Issue 2, Pages 145-158 (March 2014) DOI: 10.1016/j.jmoldx.2013.11.005 Copyright © 2014 American Society for Investigative Pathology and the Association for Molecular Pathology Terms and Conditions

Figure 1 Distribution of cytogenetic findings in myelodysplastic syndromes. Based on data from Table 2 in Schanz et al.9 The Journal of Molecular Diagnostics 2014 16, 145-158DOI: (10.1016/j.jmoldx.2013.11.005) Copyright © 2014 American Society for Investigative Pathology and the Association for Molecular Pathology Terms and Conditions

Figure 2 Mutations that affect the fundamental pathway of transcription, RNA splicing, and ribosomal biogenesis. DNA in a steady state of transcriptional regulation (middle) is subject to methylation (top) and histone modification (bottom). DNMTs methylate DNA, reducing transcription; mutation of DNMT3A (one of the genes encoding a DMNT) affects this process. TET2 mediates a step in the opposite process, removing DNA methylations; mutations of the TET2 gene lead to a loss of this demethylation function. IDH1/2 mutations result in altered enzymatic function and production of 2-hydroxyglutarate, which inhibits TET2. Histones (green balls) reduce transcription through increased binding. Histone deacetylases (HDACs) and EZH2 modify histone acetylation (red lines) and methylation (magenta circles), resulting in increased histone avidity for DNA and reduced transcription. Mutations of EZH2 and ASXL1 lead to dysregulation of histone modification. The spliceosome processes mRNA, removing introns (blue lines); genes encoding proteins that constitute the splicing machinery [SF3B1, U2AF1 (alias U2AF35), ZRSR2, and SRSF2] are mutated in MDS (Table 4) and may result in aberrant splicing. mRNA processing adds the 5′ methyl guanine cap (tan box) and the polyalanine tail (green line). Ribosomal proteins, including RPS14(5q-syndrome), RPS19(DBA), and SBDS, play roles in ribosomes (blue ovals), translating mRNA into protein; these ribosomal genes are targeted in 5q− syndrome and in hereditary bone marrow failure syndromes (eg, Diamond–Blackfan anemia and Shwachman–Bodian–Diamond syndrome). The Journal of Molecular Diagnostics 2014 16, 145-158DOI: (10.1016/j.jmoldx.2013.11.005) Copyright © 2014 American Society for Investigative Pathology and the Association for Molecular Pathology Terms and Conditions

Figure 3 Diagnostic algorithm summarizing the genetic testing modalities that are of value in MDS. Additional studies are not currently routinely used, but are poised to enter into routine testing in the near future. aCGH and/or SNP mutation testing might include a targeted panel of approximately 5 to 20 genes. The Journal of Molecular Diagnostics 2014 16, 145-158DOI: (10.1016/j.jmoldx.2013.11.005) Copyright © 2014 American Society for Investigative Pathology and the Association for Molecular Pathology Terms and Conditions