Intriguing But Yet Doable Vorinostat Practices

Mutations in these genes may represent cooperating events that are capable of interacting with several different initiating mutations. Thirteen genes were recurrently mutated only in M1 genomes (NPM1, DNMT3A, IDH1, TET2, IDH2, RUNX1, ASXL1, PTPN11, DIS3, KIT, SMC1A, SMC3, and STAG2) ( Figure?5A), suggesting that they might be involved with AML initiation. Of this group, six had mutation selleck chemical frequencies that were statistically higher in M1 versus M3 patients (NPM1, p?selleck from the TCGA AML study (Figure?5A and Table S3). Most of the genes (20/23) were recurrently mutated in these additional samples, suggesting that these mutations may participate in the pathogenesis of other AML subtypes, as expected. Some genes with low mutation frequencies in the M1 and M3 cases were not recurrently mutated in the 131 additional cases (e.g., ANKRD24, DIS3, and Ribonucleotide reductase PML-RARA), but none of the differences were statistically significant. Three of the recurrently mutated genes, STAG2, SMC3, and SMC1A, are members of the cohesin complex, which is a tetrameric structure that also includes RAD21; this complex is involved in sister chromatid separation during anaphase, and CTCF-mediated chromatin topologic constraints ( Carretero et?al., 2010; Millau and Gaudreau, 2011). STAG2 was recently found to be deleted in an AML genome ( Walter et?al., 2009) and in cancer cell lines ( Rocquain et?al., 2010; Solomon et?al.,?2011). We therefore assessed all four genes for mutations in a larger set of 183 AML samples subjected to exome or whole-genome sequencing as a part of The Cancer Genome Atlas (TCGA) study of AML (T.J.L., and R.K.W., unpublished data). We identified mutations in all four cohesin complex genes, whereas the related genes STAG1 and STAG3 were not mutated ( Figure?5E).