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

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.

SUBMITTER: Erarslan-Uysal B

PROVIDER: S-EPMC7507092 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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

Erarslan-Uysal Büşra B Kunz Joachim B JB Rausch Tobias T Richter-Pechańska Paulina P van Belzen Ianthe Aem IA Frismantas Viktoras V Bornhauser Beat B Ordoñez-Rueada Diana D Paulsen Malte M Benes Vladimir V Stanulla Martin M Schrappe Martin M Cario Gunnar G Escherich Gabriele G Bakharevich Kseniya K Kirschner-Schwabe Renate R Eckert Cornelia C Loukanov Tsvetomir T Gorenflo Matthias M Waszak Sebastian M SM Bourquin Jean-Pierre JP Muckenthaler Martina U MU Korbel Jan O JO Kulozik Andreas E AE

EMBO molecular medicine 20200805 9

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 developmenta ...[more]

PMID: 32755029

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Project description:BackgroundTrisomy 18 syndrome (Edwards syndrome, ES) is a type of aneuploidy caused by the presence of an extra chromosome 18. Aneuploidy is the leading cause of early pregnancy loss, intellectual disability, and multiple congenital anomalies. The research of trisomy 18 is progressing slowly, and the molecular characteristics of the disease mechanism and phenotype are still largely unclear.ResultsIn this study, we used the commercial Chromium platform (10× Genomics) to perform sc-ATAC-seq to measure chromatin accessibility in 11,611 single umbilical cord blood cells derived from one trisomy 18 syndrome patient and one healthy donor. We obtained 13 distinct major clusters of cells and identified them as 6 human umbilical cord blood mononuclear cell types using analysis tool. Compared with the NC group, the ES group had a lower ratio of T cells to NK cells, the ratio of monocytes/DC cell population did not change significantly, and the ratio of B cell nuclear progenitor and megakaryocyte erythroid cells was higher. The differential genes of ME-0 are enriched in Human T cell leukemia virus 1 infection pathway, and the differential peak genes of ME-1 are enriched in apopotosis pathway. We found that CCNB2 and MCM3 may be vital to the development of trisomy 18. CCNB2 and MCM3, which have been reported to be essential components of the cell cycle and chromatin.ConclusionsWe have identified 6 cell populations in cord blood. Disorder in megakaryocyte erythroid cells implicates trisomy 18 in perturbing fetal hematopoiesis. We identified a pathway in which the master differential regulatory pathway in the ME-0 cell population involves human T cell leukemia virus 1 infection, a pathway that is dysregulated in patients with trisomy 18 and which may increase the risk of leukemia in patients with trisomy 18. CCNB2 and MCM3 in progenitor may be vital to the development of trisomy 18. CCNB2 and MCM3, which have been reported to be essential components of the cell cycle and chromatin, may be related to chromosomal abnormalities in trisomy 18.

Dataset Information

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

Publications

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

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