Editors' ChoiceCancer

With This Ring

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Science Translational Medicine  26 Oct 2011:
Vol. 3, Issue 106, pp. 106ec172
DOI: 10.1126/scitranslmed.3003337

Most people propose with a diamond ring, and some propose without a ring. Proposing with a rusty iron ring does not seem such a great idea. However, new research suggests that iron rings when combined with a special mutated gene might be a favorable sign in myelodysplastic syndromes (MDS). In MDS, the presence of erythroblasts with a ring of iron-laden mitochondria around the nucleus, called ring sideroblasts (RS), usually correlates with better prognosis.

MDS are clonal hematopoietic stem cell malignancies with highly variable natural histories. They are clinically characterized by hyper- or hypocellular bone marrow with peripheral blood cytopenias and cell function abnormalities resulting from failure of hematopoietic differentiation. Patients most frequently succumb to disease after transformation to acute myelogenous leukemia (AML) or bone marrow failure. In approximately a quarter of MDS patients, RS can be found in bone marrow aspirates with special iron staining.

Papaemmanuil and colleagues found 64 point mutations in nine patients with low-grade MDS. In six of the nine patients, somatic mutations in SF3B1 (RNA splicing factor 3B, subunit 1) were identified, and targeted resequencing confirmed the presence of recurrent mutations in the SF3B1 gene in 20% of 354 MDS patients. Intriguingly, SF3B1 mutations were much more common (65%) in MDS patients with RS; less than 10% of other hematologic malignancies or solid tumors carried these mutations. The SF3B1 protein is an essential component of the spliceosome, which is a construct of five small nuclear ribonucleoproteins (snRNPs) that splices messenger RNA. Interestingly, genes involved in the mitochondrial ribosome and in the mitochondrial electron transport chain were significantly down-regulated in MDS patients with SF3B1 mutations. Finally and more importantly, MDS patients with an SF3B1 mutation, as compared with those without the mutation, had statistically significantly longer overall survival and leukemia-free survival even after adjustment for the effects of age, gender, and karyotype. As in marriage proposals, the ring can make all the difference.

E. Papaemmanuil et al., Somatic SF3B1 mutation in myelodysplasia with ring sideroblasts. N. Engl. J. Med. 365, 1384–1395 (2011). [Abstract]

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