title: Distinct iron architecture in SF3B1-mutant myelodysplastic syndrome patients is linked to an SLC25A37 splice variant with a retained intron.
abstract: Perturbation in iron homeostasis is a hallmark of some hematologic diseases. Abnormal sideroblasts with accumulation of iron in the mitochondria are named ring sideroblasts (RS). RS is a cardinal feature of refractory anemia with RS (RARS) and RARS with marked thrombocytosis (RARS/-T). Mutations in SF3B1, a member of the RNA splicing machinery are frequent in RARS/-T and defects of this gene were linked to RS formation. Here we showcase the differences in iron architecture of SF3B1-mutant and wild-type (WT) RARS/-T and provide new mechanistic insights by which SF3B1 mutations lead to differences in iron. We found higher iron levels in SF3B1 mutant vs WT RARS/-T by transmission electron microscopy/spectroscopy/flow cytometry. SF3B1 mutations led to increased iron without changing the valence as shown by the presence of Fe(2+) in mutant and WT. Reactive oxygen species and DNA damage were not increased in SF3B1-mutant patients. RNA-sequencing and Reverse transcriptase PCR showed higher expression of a specific isoform of SLC25A37 in SF3B1-mutant patients, a crucial importer of Fe(2+) into the mitochondria. Our studies suggest that SF3B1 mutations contribute to cellular iron overload in RARS/-T by deregulating SLC25A37.
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: V
authors.initials: V
authors.lastname: Visconte
authors.affiliation: Department of Materials Science and Engineering, Swagelok Center for Surface Analysis of Materials, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: N
authors.initials: N
authors.lastname: Avishai
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: R
authors.initials: R
authors.lastname: Mahfouz
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: A
authors.initials: A
authors.lastname: Tabarroki
authors.affiliation: Department of Materials Science and Engineering, Swagelok Center for Surface Analysis of Materials, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: J
authors.initials: J
authors.lastname: Cowen
authors.affiliation: Department of Materials Science and Engineering, Swagelok Center for Surface Analysis of Materials, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: R
authors.initials: R
authors.lastname: Sharghi-Moshtaghin
authors.affiliation: Electron Microscopy Facility, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: M
authors.initials: M
authors.lastname: Hitomi
authors.affiliation: Department of Clinical Pathology, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: H J
authors.initials: HJ
authors.lastname: Rogers
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: E
authors.initials: E
authors.lastname: Hasrouni
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: J
authors.initials: J
authors.lastname: Phillips
authors.affiliation: 1] Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA [2] Leukemia Program, Department of Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Sekeres
authors.affiliation: Department of Materials Science and Engineering, Swagelok Center for Surface Analysis of Materials, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: A H
authors.initials: AH
authors.lastname: Heuer
authors.affiliation: 1] Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA [2] Leukemia Program, Department of Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Saunthararajah
authors.affiliation: Department of Quantitative Health Sciences, Cleveland Clinic, OH, USA.
authors.forename: J
authors.initials: J
authors.lastname: Barnard
authors.affiliation: 1] Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA [2] Leukemia Program, Department of Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: R V
authors.initials: RV
authors.lastname: Tiu
mesh_terms: D016022:Case-Control Studies; D027682:Cation Transport Proteins / Q000235:genetics*; D004249:DNA Damage; D005434:Flow Cytometry; D006801:Humans; D007438:Introns; D007501:Iron / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics*; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics*; D012326:RNA Splicing; D000072260:RNA Splicing Factors; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017413:Ribonucleoprotein, U2 Small Nuclear / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D027682:Cation Transport Proteins; D024101:Mitochondrial Proteins; D010750:Phosphoproteins; D000072260:RNA Splicing Factors; D017382:Reactive Oxygen Species; D017413:Ribonucleoprotein, U2 Small Nuclear; C112491:SF3B1 protein, human; C561492:Slc25a37 protein, human; D007501:Iron