SF3B1, a splicing factor is frequently mutated in refractory anemia with ring sideroblasts (original) (raw)

Leukemia volume 26, pages 542–545 (2012)Cite this article

Foci of iron deposition in the perinuclear mitochondria of erythroid precursors, called ring sideroblasts (RS), can be seen in acquired and congenital cases of anemia. In many patients with myelodysplastic/myeloproliferative neoplasm (MDS/MPN) and myelodysplastic syndrome (MDS), various frequencies of RS can be found when stained with Prussian blue.1 The finding of >15% RS together with the appropriate morphologic and cytogenetic criteria is consistent with the diagnosis of refractory anemia with RS (RARS).2 RS can be also found in a form of MDS/MPN called refractory anemia with RS associated with marked thrombocytosis (RARS-T). Patients with RARS and RARS-T were also found to have mutations in JAK2, MPL, TET2 and ASXL1.3, 4, 5, 6, 7, 8 However, the clinical relevance and etiology of RS in MDS and MDS/MPN remain unclear due to the lack of specific molecular defects, including recurrent chromosomal abnormalities or mutations. High throughput-next generation sequencing (HT-NGS) is being widely used to identify mutational events in leukemia and other cancers.9 We applied this technology to patients with various forms of MDS; using this approach, we found a somatic mutation in SF3B1, a gene located in chromosome 2q in a patient with RARS and high platelet counts. SF3B1, splicing factor 3b, subunit 1, is a component of the U2-small nuclear ribonucleoprotein (U2-snRNP) complex. U2–snRNP complex is one of the two unique spliceosomes present in eukaryotic cells. It consists of SF3b, SF3a and U2-snRNP-specific proteins.10 Approximately 95% of messenger RNAs (mRNAs) have intronic regions that require further modification by spliceosomes to produce normal mRNAs. Aberrant splicing and mutations of these splicing mechanisms have been described in cancer.11, 12

We next noticed that patients harboring SF3B1 mutations are mainly RARS with normal and elevated platelet counts. We found a statistically significantly higher frequency of arterial and venous thrombotic events in patients who carry SF3B1 mutations. For 15 patients with complete clinical information regarding thrombotic events, 6 out of 10 patients with mutations had thrombotic events (_P_=0.04). None of the four wild-type patients studied had any thrombotic events. A majority of the patients are still alive with no statistically significant difference in median survival between mutant carriers and wild-type cases, a fact not surprising due to good overall prognosis of patients with RARS.

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Acknowledgements

The work was supported by Celgene Future Leaders of Hematology Award and Cleveland Clinic Institutional Seed Support (RVT); National Institutes of Health grants R01-HL082983 (JPM), U54-RR019391 (JPM and MAS) and K24-HL077522 (JPM); and a charitable donation from Robert Duggan Cancer Research Foundation. The Framingham Heart Study is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with Boston University (contract no. N01-HC-25195). This manuscript was not prepared in collaboration with investigators of the Framingham Heart Study and does not necessarily reflect the opinions or views of the Framingham Heart Study, Boston University or NHLBI.

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  1. Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
    V Visconte, H Makishima, A Jankowska, H Szpurka, F Traina, A Jerez, C O'Keefe, M A Sekeres, J P Maciejewski & R V Tiu
  2. Hematology and Hemotherapy Center, National Institute of Blood, School of Medical Sciences, University of Campinas, Campinas, Brazil
    F Traina
  3. Department of Clinical Pathology, Cleveland Clinic, Cleveland, OH, USA
    H J Rogers
  4. Department of Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
    M A Sekeres, J P Maciejewski & R V Tiu

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  1. V Visconte
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  2. H Makishima
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  3. A Jankowska
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  6. A Jerez
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Visconte, V., Makishima, H., Jankowska, A. et al. SF3B1, a splicing factor is frequently mutated in refractory anemia with ring sideroblasts.Leukemia 26, 542–545 (2012). https://doi.org/10.1038/leu.2011.232

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