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

• Verfasst von: Erarslan-Uysal, Büşra [VerfasserIn]
• Verfasst von: Kunz, Joachim [VerfasserIn]
• Verfasst von: Richter-Pechańska, Paulina [VerfasserIn]
• Verfasst von: Loukanov, Tsvetomir [VerfasserIn]
• Verfasst von: Gorenflo, Matthias [VerfasserIn]
• Verfasst von: Muckenthaler, Martina [VerfasserIn]
• Verfasst von: Kulozik, Andreas [VerfasserIn]
• Titel: Chromatin accessibility landscape of pediatric T-lymphoblastic leukemia and human T-cell precursors
• Verf.angabe: 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
• E-Jahr: 2020
• Jahr: 5 August 2020
• Umfang: 14 S.
• Fussnoten: Gesehen am 01.02.2021
• Titel Quelle: Enthalten in: European Molecular Biology OrganizationEMBO molecular medicine
• Ort Quelle: Weinheim : Wiley-VCH, 2009
• Jahr Quelle: 2020
• Band/Heft Quelle: 12(2020,9) Artikel-Nummer e12104, 14 Seiten
• ISSN Quelle: 1757-4684
• DOI: doi:10.15252/emmm.202012104
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: ATAC-Seq
• Sach-SW: chromatin accessibility
• Sach-SW: T-cell development
• Sach-SW: T-cell leukemia
• K10plus-PPN: 1746390077
• K10plus-PPN:
  Universitätsbibliothek
• Lokale URL UB: Zum Volltext

Abstract

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.