title: SF3B1 haploinsufficiency leads to formation of ring sideroblasts in myelodysplastic syndromes.
abstract: 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.
authors: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, OH, USA.
authors: Valeria
authors: V
authors: Visconte
authors: Heesun J
authors: HJ
authors: Rogers
authors: Jarnail
authors: J
authors: Singh
authors: John
authors: J
authors: Barnard
authors: Manoj
authors: M
authors: Bupathi
authors: Fabiola
authors: F
authors: Traina
authors: James
authors: J
authors: McMahon
authors: Hideki
authors: H
authors: Makishima
authors: Hadrian
authors: H
authors: Szpurka
authors: Anna
authors: A
authors: Jankowska
authors: Andres
authors: A
authors: Jerez
authors: Mikkael A
authors: MA
authors: Sekeres
authors: Yogen
authors: Y
authors: Saunthararajah
authors: Anjali S
authors: AS
authors: Advani
authors: Edward
authors: E
authors: Copelan
authors: Haruhiko
authors: H
authors: Koseki
authors: Kyoichi
authors: K
authors: Isono
authors: Richard A
authors: RA
authors: Padgett
authors: Sami
authors: S
authors: Osman
authors: Kazunori
authors: K
authors: Koide
authors: Christine
authors: C
authors: O'Keefe
authors: Jaroslaw P
authors: JP
authors: Maciejewski
authors: Ramon V
authors: RV
authors: Tiu
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000756:Anemia, Sideroblastic / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D020869:Gene Expression Profiling; D057895:Haploinsufficiency; D006801:Humans; D020014:K562 Cells; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009190:Myelodysplastic Syndromes / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D000072260:RNA Splicing Factors; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017413:Ribonucleoprotein, U2 Small Nuclear / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D010750:Phosphoproteins; D000072260:RNA Splicing Factors; D012333:RNA, Messenger; D017413:Ribonucleoprotein, U2 Small Nuclear; C112491:SF3B1 protein, human; C491799:Sf3b1 protein, mouse