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. Synopsis Analysis of chromatin accessibility of human T‐cell precursors revealed progressive chromatin condensation during maturation. Pediatric T‐ALLs resemble the most immature populations indicating that the epigenetic landscape of this type of leukemia is most similar to the earliest thymic precursors. The chromatin of differentiating human thymocytes becomes gradually condensed during maturation. Human T‐cell differentiation leaves a detectable signature in genome‐wide chromatin accessibility, which can be used to predict thymocyte maturation stage. The chromatin architecture and TF binding motif accessibility of pediatric T‐ALLs exhibit the highest resemblance to the most immature thymic precursors. Integration of ATAC‐Seq and RNA‐Seq identifies differentially accessible and expressed genes in T‐cell leukemias in comparison to healthy T‐cell precursors. Pediatric T‐ALLs either exhibit hyper‐accessibility of DAB1 overexpressing an atypical isoform, or hyper‐accessibility of SPI1(PU.1) binding motifs as well as SPI1 overexpression.
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