Evidence for a role of RUNX1 as recombinase cofactor for TCRβ rearrangements and pathological deletions in ETV6-RUNX1 ALL
| Autor: | A. Dröge, S. Schaper, Elizabeth Macintyre, Volkhard Seitz, N. Bedjaoui, Lora Dimitrova, Markus M. Heimesaat, Dido Lenze, Claudia D. Baldus, Maria Joosten, Erika Berg, Michael Hummel, C. Stocking, Anke Sommerfeld, U. Müller, Karsten Kleo, Sefer Elezkurtaj, S. Hennig, E. von der Wall, Christian Zinser, Agata Cieslak |
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| Přispěvatelé: | Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], HS Diagnomics GmbH [Berlin, Allemagne], Laboratoire d'Onco-Hematology [Paris], Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Heinrich Pette Institute [Hamburg], University Medical Center of Schleswig–Holstein = Universitätsklinikum Schleswig-Holstein (UKSH), Kiel University, Precigen Bioinformatics Germany GmbH [Munich, Allemagne], Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), The work was supported by Investitionsbank Berlin and the European Regional Development Fund (10155447 and 10155355 to the Charité and HS Diagnomics, respectively) and the Berlin Cancer Society (HUFF201629)., Bodescot, Myriam, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité) |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology
0301 basic medicine Evolution Molecular biology Receptors Antigen T-Cell alpha-beta T-Lymphocytes lcsh:Medicine Chromosomal translocation Thymus Gland Biology [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry Molecular Biology/Molecular biology Article 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine hemic and lymphatic diseases Recombinase Animals T-cell receptor Lymphocyte Count Gene Rearrangement beta-Chain T-Cell Antigen Receptor lcsh:Science Transcription factor Gene Cancer Mice Knockout B-Lymphocytes Multidisciplinary Proto-Oncogene Proteins c-ets lcsh:R [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry Molecular Biology/Molecular biology [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology Gene rearrangement Precursor Cell Lymphoblastic Leukemia-Lymphoma Repressor Proteins 030104 developmental biology RUNX1 chemistry 030220 oncology & carcinogenesis Core Binding Factor Alpha 2 Subunit embryonic structures lcsh:Q Chromatin immunoprecipitation Gene Deletion DNA |
| Zdroj: | Scientific Reports, Vol 10, Iss 1, Pp 1-16 (2020) Scientific Reports Scientific Reports, Nature Publishing Group, 2020, 10 (1), pp.10024. ⟨10.1038/s41598-020-65744-0⟩ Scientific Reports, 2020, 10 (1), pp.10024. ⟨10.1038/s41598-020-65744-0⟩ |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/s41598-020-65744-0 |
| Popis: | T-cell receptor gene beta (TCRβ) gene rearrangement represents a complex, tightly regulated molecular mechanism involving excision, deletion and recombination of DNA during T-cell development. RUNX1, a well-known transcription factor for T-cell differentiation, has recently been described to act in addition as a recombinase cofactor for TCRδ gene rearrangements. In this work we employed a RUNX1 knock-out mouse model and demonstrate by deep TCRβ sequencing, immunostaining and chromatin immunoprecipitation that RUNX1 binds to the initiation site of TCRβ rearrangement and its homozygous inactivation induces severe structural changes of the rearranged TCRβ gene, whereas heterozygous inactivation has almost no impact. To compare the mouse model results to the situation in Acute Lymphoblastic Leukemia (ALL) we analyzed TCRβ gene rearrangements in T-ALL samples harboring heterozygous Runx1 mutations. Comparable to the Runx1+/− mouse model, heterozygous Runx1 mutations in T-ALL patients displayed no detectable impact on TCRβ rearrangements. Furthermore, we reanalyzed published sequence data from recurrent deletion borders of ALL patients carrying an ETV6-RUNX1 translocation. RUNX1 motifs were significantly overrepresented at the deletion ends arguing for a role of RUNX1 in the deletion mechanism. Collectively, our data imply a role of RUNX1 as recombinase cofactor for both physiological and aberrant deletions. |
| Databáze: | OpenAIRE |
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