Blood Journal
Leading the way in experimental and clinical research in hematology

SF3B1 haploinsufficiency leads to formation of ring sideroblasts in myelodysplastic syndromes

  1. Valeria Visconte1,
  2. Heesun J. Rogers2,
  3. Jarnail Singh3,
  4. John Barnard4,
  5. Manoj Bupathi1,
  6. Fabiola Traina5,
  7. James McMahon6,
  8. Hideki Makishima1,
  9. Hadrian Szpurka1,
  10. Anna Jankowska1,
  11. Andres Jerez1,
  12. Mikkael A. Sekeres1,7,
  13. Yogen Saunthararajah1,7,
  14. Anjali S. Advani7,
  15. Edward Copelan7,
  16. Haruhiko Koseki8,
  17. Kyoichi Isono8,
  18. Richard A. Padgett3,
  19. Sami Osman9,
  20. Kazunori Koide9,
  21. Christine O'Keefe1,
  22. Jaroslaw P. Maciejewski1,7, and
  23. Ramon V. Tiu1,7
  1. 1Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH;
  2. 2Department of Clinical Pathology, Cleveland Clinic, Cleveland, OH;
  3. 3Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, OH;
  4. 4Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH;
  5. 5Hematology and Hemotherapy Center, National Institute of Blood, School of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil;
  6. 6Department of Anatomic Pathology, Cleveland Clinic, Cleveland, OH;
  7. 7Department of Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH;
  8. 8RIKEN Research Center for Allergy and Immunology, Yokohama, Japan; and
  9. 9Department of Chemistry, University of Pittsburgh, Pittsburgh, PA


Whole exome/genome sequencing has been fundamental in the identification of somatic mutations in the spliceosome machinery in myelodysplastic syndromes (MDSs) and other hematologic disorders. SF3B1, splicing factor 3b subunit 1 is mutated in 60%-80% of refractory anemia with ring sideroblasts (RARS) and RARS associated with thrombocytosis (RARS-T), 2 distinct subtypes of MDS and MDS/myeloproliferative neoplasms (MDSs/MPNs). An idiosyncratic feature of RARS/RARS-T is the presence of abnormal sideroblasts characterized by iron overload in the mitochondria, called RS. Based on the high frequency of mutations of SF3B1 in RARS/RARS-T, we investigated the consequences of SF3B1 alterations. Ultrastructurally, SF3B1 mutants showed altered iron distribution characterized by coarse iron deposits compared with wild-type RARS patients by transmission electron microscopy. SF3B1 knockdown experiments in K562 cells resulted in down-regulation of U2-type intron-splicing by RT-PCR. RNA-sequencing analysis of SF3B1 mutants showed differentially used genes relevant in MDS pathogenesis, such as ASXL1, CBL, EZH, and RUNX families. A SF3B pharmacologic inhibitor, meayamycin, induced the formation of RS in healthy BM cells. Further, BM aspirates of Sf3b1 heterozygous knockout mice showed RS by Prussian blue. In conclusion, we report the first experimental evidence of the association between SF3B1 and RS phenotype. Our data suggest that SF3B1 haploinsufficiency leads to RS formation.

  • Submitted May 16, 2012.
  • Accepted July 12, 2012.
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