Chromatin accessibility landscape of pediatric T-lymphoblastic leukemia and human T-cell precursors.
Büşra Erarslan-UysalJoachim B KunzTobias RauschPaulina Richter-PechańskaIanthe Aem van BelzenViktoras FrismantasBeat BornhauserDiana Ordoñez-RueadaMalte PaulsenVladimir BenesMartin StanullaMartin SchrappeGunnar CarioGabriele EscherichKseniya BakharevichRenate Kirschner-SchwabeCornelia EckertTsvetomir LoukanovMatthias GorenfloSebastian M WaszakJean-Pierre BourquinMartina U MuckenthalerJan O KorbelAndreas E KulozikPublished in: EMBO molecular medicine (2020)
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.
Keyphrases
- genome wide
- single cell
- rna seq
- dna damage
- gene expression
- transcription factor
- dna methylation
- endothelial cells
- induced apoptosis
- acute myeloid leukemia
- copy number
- end stage renal disease
- cell cycle arrest
- bone marrow
- randomized controlled trial
- dna binding
- peritoneal dialysis
- newly diagnosed
- clinical trial
- cell proliferation
- endoplasmic reticulum stress
- prognostic factors
- young adults
- genetic diversity