Chromatin accessibility landscape of pediatric T-lymphoblastic leukemia and human T-cell precursors.
EMBO Mol Med
; 12(9): e12104, 2020 09 07.
Article
em En
| MEDLINE
| ID: mdl-32755029
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.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Células Precursoras de Linfócitos T
/
Leucemia-Linfoma Linfoblástico de Células T Precursoras
Limite:
Child
/
Humans
Idioma:
En
Revista:
EMBO Mol Med
Assunto da revista:
BIOLOGIA MOLECULAR
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Alemanha