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Evidence for a role of RUNX1 as recombinase cofactor for TCRβ rearrangements and pathological deletions in ETV6-RUNX1 ALL
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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308335/ https://www.ncbi.nlm.nih.gov/pubmed/32572036 http://dx.doi.org/10.1038/s41598-020-65744-0 |
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author | Seitz, V. Kleo, K. Dröge, A. Schaper, S. Elezkurtaj, S. Bedjaoui, N. Dimitrova, L. Sommerfeld, A. Berg, E. von der Wall, E. Müller, U. Joosten, M. Lenze, D. Heimesaat, M. M. Baldus, C. Zinser, C. Cieslak, A. Macintyre, E. Stocking, C. Hennig, S. Hummel, M. |
author_facet | Seitz, V. Kleo, K. Dröge, A. Schaper, S. Elezkurtaj, S. Bedjaoui, N. Dimitrova, L. Sommerfeld, A. Berg, E. von der Wall, E. Müller, U. Joosten, M. Lenze, D. Heimesaat, M. M. Baldus, C. Zinser, C. Cieslak, A. Macintyre, E. Stocking, C. Hennig, S. Hummel, M. |
author_sort | Seitz, V. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7308335 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-73083352020-06-23 Evidence for a role of RUNX1 as recombinase cofactor for TCRβ rearrangements and pathological deletions in ETV6-RUNX1 ALL Seitz, V. Kleo, K. Dröge, A. Schaper, S. Elezkurtaj, S. Bedjaoui, N. Dimitrova, L. Sommerfeld, A. Berg, E. von der Wall, E. Müller, U. Joosten, M. Lenze, D. Heimesaat, M. M. Baldus, C. Zinser, C. Cieslak, A. Macintyre, E. Stocking, C. Hennig, S. Hummel, M. Sci Rep Article 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. Nature Publishing Group UK 2020-06-22 /pmc/articles/PMC7308335/ /pubmed/32572036 http://dx.doi.org/10.1038/s41598-020-65744-0 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Seitz, V. Kleo, K. Dröge, A. Schaper, S. Elezkurtaj, S. Bedjaoui, N. Dimitrova, L. Sommerfeld, A. Berg, E. von der Wall, E. Müller, U. Joosten, M. Lenze, D. Heimesaat, M. M. Baldus, C. Zinser, C. Cieslak, A. Macintyre, E. Stocking, C. Hennig, S. Hummel, M. Evidence for a role of RUNX1 as recombinase cofactor for TCRβ rearrangements and pathological deletions in ETV6-RUNX1 ALL |
title | Evidence for a role of RUNX1 as recombinase cofactor for TCRβ rearrangements and pathological deletions in ETV6-RUNX1 ALL |
title_full | Evidence for a role of RUNX1 as recombinase cofactor for TCRβ rearrangements and pathological deletions in ETV6-RUNX1 ALL |
title_fullStr | Evidence for a role of RUNX1 as recombinase cofactor for TCRβ rearrangements and pathological deletions in ETV6-RUNX1 ALL |
title_full_unstemmed | Evidence for a role of RUNX1 as recombinase cofactor for TCRβ rearrangements and pathological deletions in ETV6-RUNX1 ALL |
title_short | Evidence for a role of RUNX1 as recombinase cofactor for TCRβ rearrangements and pathological deletions in ETV6-RUNX1 ALL |
title_sort | evidence for a role of runx1 as recombinase cofactor for tcrβ rearrangements and pathological deletions in etv6-runx1 all |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308335/ https://www.ncbi.nlm.nih.gov/pubmed/32572036 http://dx.doi.org/10.1038/s41598-020-65744-0 |
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