Somatic SF3B1 Mutation in Myelodysplasia with Ring Sideroblasts

Chronic Myeloid Disorders Working Group of the International Cancer Genome Consortium.-- et al.The myelodysplastic syndromes are a heterogeneous group of hematologic cancers characterized by low blood counts, most commonly anemia, and a risk of progression to acute myeloid leukemia.1 These disorders have increased in prevalence and are expected to continue to do so. Blood films and bone marrow¿biopsy specimens from patients with myelodysplastic syndromes show dysplastic changes in myeloid cells, with abnormal proliferation and differentiation of one or more lineages. Target genes of recurrent chromosomal aberrations have been mapped,2,3 and several genes have been identified as recurrently mutated in these disorders, including NRAS (encoding neuroblastoma RAS viral oncogene homologue), TP53 (encoding tumor protein p53), RUNX1 (encoding runt-related transcription factor 1), CBL (encoding Cas-Br-M ecotropic retroviral transforming sequence),4,5 TET2 (encoding tet oncogene family member 2),6,7 ASXL1 (encoding additional sex combs¿like protein 1),8,9 and EZH2 (encoding enhancer of zeste homologue 2).10 With the exception of TET2, most of these genes are mutated in no more than 5 to 15% of cases, and generally the mutation rates are lower in the more benign subtypes of the disease. The myelodysplastic syndromes can be divided into several categories on the basis of bone marrow and peripheral-blood morphologic characteristics and cytogenetic changes.11 In low-risk disease, such as refractory anemia, cytopenias are the major clinical challenge, whereas high-risk disease, such as refractory anemia with excess blasts, is characterized by both cytopenias and a high rate of transformation to acute myeloid leukemia. More than a quarter of patients with myelodysplastic syndromes have large numbers of ring sideroblasts in the bone marrow,12 a sufficiently distinctive morphologic abnormality to warrant a separate designation. Ring sideroblasts are characteristically seen on iron staining of bone marrow aspirates as differentiating erythroid cells with a complete or partial ring of iron-laden mitochondria surrounding the nucleus. Several genetic lesions underpinning inherited sideroblastic anemias have been identified,13 including loss-of-function mutations in the genes ALAS2 (encoding delta aminolevulinate synthase 2), ABCB7 (encoding ATP-binding cassette, subfamily B, member 7), and SLC25A38 (solute carrier family 25, member 38). The pathogenesis of ring sideroblasts in myelodysplastic syndromes, however, remains obscure, although gene-expression studies have revealed up-regulation of genes involved in heme synthesis (including ALAS2) and down-regulation of ABCB7.14,15 We reasoned that the identification of recurrently mutated cancer genes in low-grade myelodysplastic syndromes could prove useful for the diagnosis of these disorders and provide new insights into the molecular pathogenesis of these syndromesSupported by grants from the Wellcome Trust (077012/Z/05/Z, for the overall study, as well as WT088340MA, to Dr. Campbell), the Kay Kendall Leukaemia Fund, Leukemia Lymphoma Research (for the overall study and to Drs. Boultwood, Green, Vyas, and Wainscoat), the Adenoid Cystic Carcinoma Research Foundation, the Medical Research Council (MRC) (to Dr. Warren), the Oxford National Institutes for Health Research Biomedical Research Centre (to Drs. Boultwood, Vyas, and Wainscoat), the Swedish Cancer Society (to Dr. Hellstrom-Lindburg), the International Human Frontier Science Program Organization (to Dr. Varela), the Department of Veterans Affairs and the National Institutes of Health (R01-124929, P01-155249, P50- 100007, and P01-78378, to Drs. Munshi and Anderson), the Association for International Cancer Research and the Leukemia Lymphoma Society (to Drs. Warren and Green), Associazione Italiana per la Ricerca sul Cancro (to the University of Pavia, the University of Milan Bicocca, and Dr. Cazzola), and Fondazione Cariplo (to the University of Pavia and the University of Milan Bicocca).Peer Reviewe