Perspectives MYELOID NEOPLASIA The genetic basis of myelodysplasia and its clinical relevance

Myelodysplasia is a diagnostic feature of myelodysplastic syndromes (MDSs) but is also found in other myeloid neoplasms. Its molecular basis has been recently elu-cidated by means of massive parallel sequencing studies. About 90 % of MDS patients carry ‡1 oncogenic mutations, and two thirds of them are found in in-dividuals with a normal karyotype. Driver mutant genes include those of RNA splic-ing (SF3B1, SRSF2, U2AF1, and ZRSR2), DNA methylation (TET2, DNMT3A, and IDH1/2), chromatin modification (ASXL1 andEZH2), transcription regulation (RUNX1), DNA repair (TP53), signal transduction (CBL, NRAS, and KRAS), and cohesin complex (STAG2). Only 4 to 6 genes are consistently mutated in ‡10 % MDS patients, whereas a long tail of ∼50 genes are mutated less frequently. At presentation, most patients typically have 2 or 3 driver oncogenic mu-tations and hundreds of background muta-tions. MDS driver genes are also frequently mutated in other myeloid neoplasms. Reli-able genotype/phenotype relationships include the association of the SF3B1 mutation with refractory anemia with ring sideroblasts, TET2/SRSF2 comutation with chronic myelomonocytic leukemia, and activating CSF3Rmutation with chronic neutrophilic leukemia. Although both founding and subclonal driver muta-tions have been shown to have prog-nostic significance, prospective clinical trials that include the molecular charac-terization of the patient’s genome are now needed. (Blood. 2013;122(25):4021-4034