<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "Epigenetic blueprint of human thymopoiesis and adult T-cell Acute Lymphoblastic Leukemia"^^ . "Thymopoiesis is a process by which bone-marrow-derived lymphoid progenitor cells migrate\r\nto the thymus and undergo multi-step differentiation into mature CD4+ or CD8+ Tlymphocytes.\r\nThe entire process is tightly regulated and governed by the\r\ntranscriptional/epigenetic changes necessary for lineage commitment and cellular identity.\r\nGenetic lesions such as somatically acquired point mutations or chromosomal rearrangements lead to differentiation blockade resulting in hematological malignancy known as T-cell acute lymphoblastic leukemia (T-ALL). While the thymopoiesis and T-ALL are\r\nwell characterized by transcriptional studies, high-resolution mapping of the epigenetic\r\nchanges is still lacking.\r\nDNA methylation (DNAm) changes involving the addition of de-novo, or the erasure of\r\nexisting methyl groups from the cytosine nucleotide, are dynamic during cellular\r\ndifferentiation and form the cell-type-specific signatures. In this doctoral thesis, DNAm\r\ndynamics during the human thymopoiesis is studied by whole-genome bisulfite sequencing\r\nof seven distinct intra-thymic cell types. DNAm changes during the thymopoiesis are\r\ncharacterized by the uni-directional and irreversible loss methylation primarily occurring at\r\nthe transcription factor binding sites critical for T-cell lineage commitment (e.g., NOTCH1 and\r\nMYB) and T-cell receptor rearrangements. A DNAm atlas of thymopoiesis is established by\r\nidentifying 381 de-novo differentially methylated regions (tDMRs) that are highly conserved\r\nacross cell-types originating from the thymic lineage. The tDMRs can recapitulate the in-silico\r\nontogeny of T-cell differentiation and are validated in an independent dataset. Remarkably,\r\ncombined analysis with bone-marrow-derived hematopoietic progenitors and peripheral\r\nderived mature blood cells shows the hypermethylation of tDMRs among non-lymphoid cell\r\ntypes suggesting the epigenetic silencing of pathways necessary for thymic lineage\r\ncommitment.\r\nTo further highlight the role of tDMRs in disease development, a combined array-centric\r\nanalysis of intra-thymic cell types and a well-defined cohort of 143 primary adult T-ALLs was\r\nperformed. Interestingly, DNAm classified the T-ALL cohort into five distinct subtypes (C1-C5)\r\nwith characteristic levels of DNAm (C1 lowest level and C5 the highest). Moreover, each\r\nII\r\nsubtype is correlated with a specific somatic event, including a novel adult T-ALL specific\r\nsubtype with co-occurring DNMT3A/IDH2 mutations (C1), and well known transcriptionally\r\nderegulated subtypes resulting from TAL1 (C2), TLX3 (C3), TLX1/in cis-HOXA9 (C4), or in trans-\r\nHOXA9 (C5) overexpression. Utilizing tDMRs as the blueprint, maturation arrest stages of TALL\r\nsubtypes are established, revealing a hierarchical ordering, with C1 and C5 arising earlier\r\nduring the T-cell development followed by TLX3/1 overexpression (C3, C4) and TAL1\r\nderegulation (C5). Although tDMRs highlight the ontogeny of T-ALL subtypes, global DNAm\r\nlevels did not correlate with the maturation arrest stages suggesting a non-linear association\r\nof DNAm and differentiation blockade. Subsequent integrative analysis with epigenetic marks\r\nassociated with active transcription (H3K27ac and H3K4me1) revealed the hypomethylation\r\nof pathogenic enhancer elements. Importantly, careful survival analysis identified an\r\nunexpected, clinically aggressive hypermethylated subtype (C5) that can be targeted with DNA\r\nhypomethylating agents. Finally, using machine learning models, a 79 CpG classifier was\r\ndeveloped for de-novo classification of newly diagnosed adult T-ALLs.\r\nIn summary, results from the comprehensive analysis of DNAm changes during human\r\nthymopoiesis and the subsequent modifications leading to T-ALL provide meaningful insights\r\ninto the role of DNAm in maintaining the cellular identity and disease development.\r\nFurthermore, the identification of clinically actionable hypermethylated T-ALL subtype paves\r\nthe way for targeted epigenetic therapies."^^ . "2021" . . . . . . . "Anand"^^ . "Mayakonda Thippeswamy"^^ . "Anand Mayakonda Thippeswamy"^^ . . . . . . "Epigenetic blueprint of human thymopoiesis and adult T-cell Acute Lymphoblastic Leukemia (PDF)"^^ . . . "Mayakonda_PhD-Thesis_2021.pdf"^^ . . . "Epigenetic blueprint of human thymopoiesis and adult T-cell Acute Lymphoblastic Leukemia (Other)"^^ . . . . . . "lightbox.jpg"^^ . . . "Epigenetic blueprint of human thymopoiesis and adult T-cell Acute Lymphoblastic Leukemia (Other)"^^ . . . . . . "preview.jpg"^^ . . . "Epigenetic blueprint of human thymopoiesis and adult T-cell Acute Lymphoblastic Leukemia (Other)"^^ . . . . . . "medium.jpg"^^ . . . "Epigenetic blueprint of human thymopoiesis and adult T-cell Acute Lymphoblastic Leukemia (Other)"^^ . . . . . . "small.jpg"^^ . . . "Epigenetic blueprint of human thymopoiesis and adult T-cell Acute Lymphoblastic Leukemia (Other)"^^ . . . . . . "indexcodes.txt"^^ . . "HTML Summary of #30220 \n\nEpigenetic blueprint of human thymopoiesis and adult T-cell Acute Lymphoblastic Leukemia\n\n" . "text/html" . . . "570 Biowissenschaften, Biologie"@de . "570 Life sciences"@en . .