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Chromatin accessibility landscape of pediatric T-lymphoblastic leukemia and human T-cell precursors

Abstract: We aimed at identifying the developmental stage at which leukemic cells of pediatric T-ALLs are arrested and at defining leukemogenic mechanisms based on ATAC-Seq. Chromatin accessibility maps of seven developmental stages of human healthy T cells revealed progressive chromatin condensatio...

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Main Authors: Erarslan-Uysal, Büşra (Author) , Kunz, Joachim (Author) , Richter-Pechańska, Paulina (Author) , Loukanov, Tsvetomir (Author) , Gorenflo, Matthias (Author) , Muckenthaler, Martina (Author) , Kulozik, Andreas (Author)
Format: Article (Journal)
Language:English
Published: 5 August 2020
In: EMBO molecular medicine
Year: 2020, Volume: 12, Issue: 9
ISSN:1757-4684
DOI:10.15252/emmm.202012104
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.15252/emmm.202012104
Verlag, kostenfrei, Volltext: https://www.embopress.org/doi/full/10.15252/emmm.202012104
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Author Notes:Büşra Erarslan-Uysal, Joachim B Kunz, Tobias Rausch, Paulina Richter-Pechańska, Ianthe AEM van Belzen, Viktoras Frismantas, Beat Bornhauser, Diana Ordoñez-Rueada, Malte Paulsen, Vladimir Benes, Martin Stanulla, Martin Schrappe, Gunnar Cario, Gabriele Escherich, Kseniya Bakharevich, Renate Kirschner-Schwabe, Cornelia Eckert, Tsvetomir Loukanov, Matthias Gorenflo, Sebastian M Waszak, Jean-Pierre Bourquin, Martina U Muckenthaler, Jan O Korbel & Andreas E Kulozik
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Summary:Abstract: We aimed at identifying the developmental stage at which leukemic cells of pediatric T-ALLs are arrested and at defining leukemogenic mechanisms based on ATAC-Seq. Chromatin accessibility maps of seven developmental stages of human healthy T cells revealed progressive chromatin condensation during T-cell maturation. Developmental stages were distinguished by 2,823 signature chromatin regions with 95% accuracy. Open chromatin surrounding SAE1 was identified to best distinguish thymic developmental stages suggesting a potential role of SUMOylation in T-cell development. Deconvolution using signature regions revealed that T-ALLs, including those with mature immunophenotypes, resemble the most immature populations, which was confirmed by TF-binding motif profiles. We integrated ATAC-Seq and RNA-Seq and found DAB1, a gene not related to leukemia previously, to be overexpressed, abnormally spliced and hyper-accessible in T-ALLs. DAB1-negative patients formed a distinct subgroup with particularly immature chromatin profiles and hyper-accessible binding sites for SPI1 (PU.1), a TF crucial for normal T-cell maturation. In conclusion, our analyses of chromatin accessibility and TF-binding motifs showed that pediatric T-ALL cells are most similar to immature thymic precursors, indicating an early developmental arrest.
Item Description:Gesehen am 01.02.2021
Physical Description:Online Resource
ISSN:1757-4684
DOI:10.15252/emmm.202012104

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