Chromatin accessibility landscape of pediatric T-lymphoblastic leukemia and human T-cell precursors
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Chromatin accessibility landscape of pediatric T-lymphoblastic leukemia and human T-cell precursors. / Erarslan-Uysal, Büşra; Kunz, Joachim B; Rausch, Tobias; Richter-Pechańska, Paulina; van Belzen, Ianthe Aem; Frismantas, Viktoras; Bornhauser, Beat; Ordoñez-Rueada, Diana; Paulsen, Malte; Benes, Vladimir; Stanulla, Martin; Schrappe, Martin; Cario, Gunnar; Escherich, Gabriele; Bakharevich, Kseniya; Kirschner-Schwabe, Renate; Eckert, Cornelia; Loukanov, Tsvetomir; Gorenflo, Matthias; Waszak, Sebastian M; Bourquin, Jean-Pierre; Muckenthaler, Martina U; Korbel, Jan O; Kulozik, Andreas E.
in: EMBO MOL MED, Jahrgang 12, Nr. 9, 07.09.2020, S. e12104.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Chromatin accessibility landscape of pediatric T-lymphoblastic leukemia and human T-cell precursors
AU - Erarslan-Uysal, Büşra
AU - Kunz, Joachim B
AU - Rausch, Tobias
AU - Richter-Pechańska, Paulina
AU - van Belzen, Ianthe Aem
AU - Frismantas, Viktoras
AU - Bornhauser, Beat
AU - Ordoñez-Rueada, Diana
AU - Paulsen, Malte
AU - Benes, Vladimir
AU - Stanulla, Martin
AU - Schrappe, Martin
AU - Cario, Gunnar
AU - Escherich, Gabriele
AU - Bakharevich, Kseniya
AU - Kirschner-Schwabe, Renate
AU - Eckert, Cornelia
AU - Loukanov, Tsvetomir
AU - Gorenflo, Matthias
AU - Waszak, Sebastian M
AU - Bourquin, Jean-Pierre
AU - Muckenthaler, Martina U
AU - Korbel, Jan O
AU - Kulozik, Andreas E
N1 - © 2020 The Authors. Published under the terms of the CC BY 4.0 license.
PY - 2020/9/7
Y1 - 2020/9/7
N2 - 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.
AB - 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.
U2 - 10.15252/emmm.202012104
DO - 10.15252/emmm.202012104
M3 - SCORING: Journal article
C2 - 32755029
VL - 12
SP - e12104
JO - EMBO MOL MED
JF - EMBO MOL MED
SN - 1757-4676
IS - 9
ER -