Mutations in the splicing factor 3b subunit 1 (SF3B1) gene are frequent in myelodysplastic neoplasms (MDS). Because the splicing process is involved in the production of circular RNAs (circRNAs), we investigated the impact of SF3B1 mutations on circRNA processing. Using RNA sequencing, we measured circRNA expression in CD34+ bone marrow MDS cells. We defined circRNAs deregulated in a heterogeneous group of MDS patients and described increased circRNA formation in higher-risk MDS. We showed that the presence of SF3B1 mutations did not affect the global production of circRNAs; however, deregulation of specific circRNAs was observed. Particularly, we demonstrated that strong upregulation of circRNAs processed from the zinc finger E-box binding homeobox 1 (ZEB1) transcription factor; this upregulation was exclusive to SF3B1-mutated patients and was not observed in those with mutations in other splicing factors or other recurrently mutated genes, or with other clinical variables. Furthermore, we focused on the most upregulated ZEB1-circRNA, hsa_circ_0000228, and, by its knockdown, we demonstrated that its expression is related to mitochondrial activity. Using microRNA analyses, we proposed miR-1248 as a direct target of hsa_circ_0000228. To conclude, we demonstrated that mutated SF3B1 leads to deregulation of ZEB1-circRNAs, potentially contributing to the defects in mitochondrial metabolism observed in SF3B1-mutated MDS.

1st Department of Medicine General University Hospital Prague Czech Republic

Department of Biochemistry Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences Prague Czech Republic

Department of Cell Biology Faculty of Science Charles University Prague Czech Republic

Department of Computer Science Czech Technical University Prague Czech Republic

Department of Genetics and Microbiology Faculty of Science Charles University Prague Czech Republic

Department of Genomics Institute of Hematology and Blood Transfusion Prague Czech Republic

Department of Immunomonitoring and Flow Cytometry Institute of Hematology and Blood Transfusion Prague Czech Republic

Department of Modern Immunotherapy Institute of Hematology and Blood Transfusion Prague Czech Republic

Department of Proteomics Institute of Hematology and Blood Transfusion Prague Czech Republic

International Clinical Research Center of St Anne's University Hospital Brno Czech Republic

Laboratory of Anemias Institute of Hematology and Blood Transfusion Prague Czech Republic

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$a Trsova, Iva $u Department of Genomics, Institute of Hematology and Blood Transfusion, Prague, Czech Republic $u Department of Genetics and Microbiology, Faculty of Science, Charles University, Prague, Czech Republic

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$a Expression of circular RNAs in myelodysplastic neoplasms and their association with mutations in the splicing factor gene SF3B1 / $c I. Trsova, A. Hrustincova, Z. Krejcik, D. Kundrat, A. Holoubek, K. Staflova, L. Janstova, S. Vanikova, K. Szikszai, J. Klema, P. Rysavy, M. Belickova, M. Kaisrlikova, J. Vesela, J. Cermak, A. Jonasova, J. Dostal, J. Fric, J. Musil, M. Dostalova Merkerova

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$a Mutations in the splicing factor 3b subunit 1 (SF3B1) gene are frequent in myelodysplastic neoplasms (MDS). Because the splicing process is involved in the production of circular RNAs (circRNAs), we investigated the impact of SF3B1 mutations on circRNA processing. Using RNA sequencing, we measured circRNA expression in CD34+ bone marrow MDS cells. We defined circRNAs deregulated in a heterogeneous group of MDS patients and described increased circRNA formation in higher-risk MDS. We showed that the presence of SF3B1 mutations did not affect the global production of circRNAs; however, deregulation of specific circRNAs was observed. Particularly, we demonstrated that strong upregulation of circRNAs processed from the zinc finger E-box binding homeobox 1 (ZEB1) transcription factor; this upregulation was exclusive to SF3B1-mutated patients and was not observed in those with mutations in other splicing factors or other recurrently mutated genes, or with other clinical variables. Furthermore, we focused on the most upregulated ZEB1-circRNA, hsa_circ_0000228, and, by its knockdown, we demonstrated that its expression is related to mitochondrial activity. Using microRNA analyses, we proposed miR-1248 as a direct target of hsa_circ_0000228. To conclude, we demonstrated that mutated SF3B1 leads to deregulation of ZEB1-circRNAs, potentially contributing to the defects in mitochondrial metabolism observed in SF3B1-mutated MDS.

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$a Hrustincova, Andrea $u Department of Genomics, Institute of Hematology and Blood Transfusion, Prague, Czech Republic

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$a Staflova, Karolina $u Department of Biochemistry, Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czech Republic

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$a Janstova, Lucie $u Department of Modern Immunotherapy, Institute of Hematology and Blood Transfusion, Prague, Czech Republic $u Department of Cell Biology, Faculty of Science, Charles University, Prague, Czech Republic

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$a Klema, Jiri $u Department of Computer Science, Czech Technical University, Prague, Czech Republic

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$a Rysavy, Petr $u Department of Computer Science, Czech Technical University, Prague, Czech Republic

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$a Jonasova, Anna $u First Department of Medicine, General University Hospital, Prague, Czech Republic

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$a Dostal, Jiri $u Department of Biochemistry, Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czech Republic

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$a Musil, Jan $u Department of Immunomonitoring and Flow Cytometry, Institute of Hematology and Blood Transfusion, Prague, Czech Republic

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