Editors' ChoiceBlood Disorders

Molecular Clue to Disease Prognosis

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Science Translational Medicine  12 Oct 2011:
Vol. 3, Issue 104, pp. 104ec166
DOI: 10.1126/scitranslmed.3003283

When one considers maladies of the aged, heart disease and neurodegeneration quickly come to mind. But cancer, too, is essentially an age-related disease, as are certain precancerous conditions. Myelodysplastic syndromes (MDSs), for example, are a heterogeneous group of abnormal blood conditions—hematological premalignancies—that commonly manifest in the elderly and in former cancer patients who have undergone radiation or cytotoxic chemotherapy. MDSs have a significant risk of transformation into acute myelogenous leukemia (AML), but there are no known molecular predictors of this progression. As a first step toward unearthing such biomarkers, Papaemmanuil et al. report results of genome-wide screens in nine MDS patients of somatic mutations across all protein-coding exons.

MDSs are disorders of the bone marrow stem cells that disrupt the development of blood cells (hematological dysplasia), leading to anemia and low blood counts. Patients often require multiple blood transfusions, and about one-third develop AML. Despite recent molecular advances in the identification of genes involved in MDS pathogenesis, classification and prognostic predictions still largely depend on morphological and cytogenetic analyses.

Using massively parallel sequencing technology, the authors identified in the nine MDS patients recurrent somatic mutations in the gene that encodes RNA splicing factor 3B, subunit 1 (SF3B1). Then in an unselected pool of 354 MDS patients, SF3B1 mutations were identified in 72 of these subjects (20%). Furthermore, in patients with ring sideroblasts—an aberrant form of red blood cells seen in MDS—the percentage of SF3B1 gene mutations was even higher (53 of 82 patients, or 65%). Structure-function analysis suggested that these mutations produced changes in the SF3B1 protein that altered its splicing function. Gene expression profiling revealed that mutations in SF3B1 were associated with selective down-regulation of genes that encode components of core mitochondrial pathways. Clinically, these patients exhibited fewer reductions in the number of blood cells and longer event-free survival than did MDS patients without these mutations. These results are encouraging with respect to future implications of molecular risk stratification for progression to AML and targeted therapies for MDS patients.

MDS represents a broad spectrum of benign to malignant diseases with continuous clonal evolution of malignant stem cells, and it remains unknown when SF3B1 mutations occur or whether they prevent transformation to AML. Indeed, the functional importance of the SF3B1 mutations described by the authors must be validated in vivo. In addition, intricate biochemical investigation is required to determine whether and how dysregulated mitochondrial pathways and RNA splicing are linked to oncogenesis. Genetic studies such as this one by Papaemmanuil et al. offer possible substrates for future mechanistic, diagnostic, and therapeutic investigations of this enigmatic heterogeneous disorder.

E. Papaemmanuil et al., Somatic SF3B1 mutation in myelodysplasia with ring sideroblasts. N. Engl. J. Med. 26 September 2011 (10.1056/NEJMoa1103283). [Abstract]

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