SF3B1 haploinsufficiency leads to formation of ring sideroblasts in myelodysplastic syndromes

dc.creatorVisconte, Valeria
dc.creatorRogers, Heesun J.
dc.creatorSingh, Jarnail
dc.creatorBarnard, John
dc.creatorBupathi, Manoj
dc.creatorTraina, Fabiola
dc.creatorMcMahon, James
dc.creatorMakishima, Hideki
dc.creatorSzpurka, Hadrian
dc.creatorJankowska, Anna
dc.creatorJerez, Andres
dc.creatorSekeres, Mikkael A.
dc.creatorSaunthararajah, Yogen
dc.creatorAdvani, Anjali S.
dc.creatorCopelan, Edward
dc.creatorKoseki, Haruhiko
dc.creatorIsono, Kyoichi
dc.creatorPadgett, Richard A.
dc.creatorOsman, Sami
dc.creatorKoide, Kazunori
dc.creatorO'Keefe, Christine
dc.creatorMaciejewski, Jaroslaw P.
dc.creatorTiu, Ramon V.
dc.date2012
dc.date2013-09-19T18:06:53Z
dc.date2016-06-21T20:06:06Z
dc.date2013-09-19T18:06:53Z
dc.date2016-06-21T20:06:06Z
dc.date.accessioned2018-03-29T01:52:33Z
dc.date.available2018-03-29T01:52:33Z
dc.identifierBlood. Amer Soc Hematology, v.120, n.16, p.3173-3186, 2012
dc.identifier0006-4971
dc.identifierWOS:000311619200008
dc.identifier10.1182/blood-2012-05-430876
dc.identifierhttp://www.repositorio.unicamp.br/jspui/handle/REPOSIP/2490
dc.identifierhttp://repositorio.unicamp.br/jspui/handle/REPOSIP/2490
dc.identifier.urihttp://repositorioslatinoamericanos.uchile.cl/handle/2250/1308183
dc.descriptionWhole 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 over-load 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 inMDSpathogenesis, 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. (Blood. 2012;120(16):3173-3186)
dc.description120
dc.description16
dc.description3173
dc.description3186
dc.descriptionCleveland Clinic Seed Support
dc.descriptionMDS Foundation
dc.descriptionAA-MDS International Foundation
dc.descriptionNational Institutes of Health [R01 HL082983, U54 RR019391, K24 HL077522, R01 CA120792, RO1 GM093074]
dc.descriptionRobert Duggan Cancer Research Foundation
dc.languageeng
dc.publisherAmer Soc Hematology
dc.publisherWashington
dc.relationBlood
dc.rightsfechado
dc.sourceWOS
dc.subjectPRE-MESSENGER-RNA
dc.subjectMYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASMS
dc.subjectMUTATIONS
dc.subjectGENES
dc.subjectMACHINERY
dc.subjectPATHWAY
dc.subjectPROTEIN
dc.subjectANEMIA
dc.subjectCELLS
dc.subjectSEQ
dc.titleSF3B1 haploinsufficiency leads to formation of ring sideroblasts in myelodysplastic syndromes
dc.typeArtículos de revistas


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