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

TY - JOUR

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 -