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    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. © 2020 The Authors. Published under the terms of the CC BY 4.0 license.

    Citation

    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. Chromatin accessibility landscape of pediatric T-lymphoblastic leukemia and human T-cell precursors. EMBO molecular medicine. 2020 Sep 07;12(9):e12104

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    PMID: 32755029

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