<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "Acute Myeloid Leukemia with deletion 5q: an epigenetic perspective"^^ . "Acute myeloid leukemia (AML) is a hematological cancer characterised by a block in differentiation and\r\naccelerated proliferation of myeloid progenitor cells. Epigenetic regulators are among the most frequent\r\ntargets for mutations and structural variations in AML, and the disruption of these genes can result in\r\nprofound epigenetic heterogeneity between and within tumors. Deletion 5q [del(5q)] is the most common\r\ncopy number alteration (CNA) in older AML patients and is associated with poor clinical outcome and\r\ntherapy resistance, however the mechanisms linking del(5q) to leukemic development and progression are\r\nnot understood.\r\nI began this thesis with an analysis of DNA methylation profiles from 477 elderly AML patients using a\r\nDNA methylome deconvolution approach. Here I discovered that del(5q) AML constitutes an\r\nepigenetically distinct subgroup characterized by a unique signature of DNA hypermethylation. In an\r\nattempt to pinpoint the epigenetic disturbance leading this signature to arise, I investigated the 5q\r\nMinimally Deleted Region (MDR) for potential epigenetic regulators, and identified the H3K9me1/2\r\ndemethylase KDM3B as a promising target. Precise mapping of the MDR, together with differential\r\ntranscriptional, protein and mutational analysis of 5q genes strengthened the argument that KDM3B is the\r\nmost likely candidate for haploinsufficiency in del(5q) AML. I further linked the del(5q) methylation\r\nsignature to dysregulation of other H3K9me1/2 regulators, and consistent overexpression of the de novo\r\nDNA methyltransferase and leukemic stem cell marker, DNMT3B. Moreover, I discovered that del(5q)\r\nand MECOM -overexpressing leukemias share a common DNA methylation signature, which in both\r\nsubgroups coincides with increased expression of DNMT3B. These findings suggest that del(5q) AML\r\ndeserves to be reappraised as an epigenetically-defined subgroup, which I suggest may be driven by\r\nhaploinsufficiency of KDM3B.\r\nReduction in protein levels of KDM3B should result in an increase in H3K9me1/2. In addition, I\r\nhypothesized that haploinsufficiency of this enzyme may result in an imbalanced removal of H3K9me1/2,\r\nsuch that variable patterns of these histone marks may arise between cells. Such cell-to-cell epigenomic\r\nheterogeneity could provide a powerful driving force for leukemic progression by allowing selection of\r\nfavorable phenotypes throughout cancer evolution and in response to therapy. To study this phenomenon,\r\nI developed a heterogeneity metric called epiCHAOS (epigenetic/Chromatin Heterogeneity Assessment\r\nOf Single cells). EpiCHAOS is the first tool that enables quantitative comparisons of epigenetic\r\nheterogeneity between single-cell groups/clusters within a biological sample. I validated epiCHAOS in\r\nsilico and demonstrated its functionality by applying the metric to a range of biological datasets from\r\ndevelopmental systems, cancers, and aging to investigate both genome-wide and region-specific\r\ndifferences in epigenetic heterogeneity.\r\nFinally, to investigate the epigenetic consequences of KDM3B disruption in AML, I analyzed single-cell\r\nassay for transposase-accessible chromatin with sequencing (ATAC-seq) data generated from\r\nKDM3B-heterozygous OCI-AML3 cell lines, which were established to mimic haploinsufficiency of the\r\nenzyme. Heterozygous deletion of KDM3B resulted in the expected global chromatin compaction as well\r\nas epigenetic heterogeneity at H3K9me1/2- associated regions.\r\nThis thesis provides two important contributions for the research community. First, my findings shed light\r\non the mechanisms driving one of the most aggressive forms of AML, which until now has not been\r\nstudied from an epigenetic perspective, and where KDM3B has received very little attention as a putative\r\ntarget gene. Secondly, I provide the first computational strategy for quantitative single-cell analysis of\r\nepigenomic heterogeneity, which should offer a useful tool for biologists, especially those interested in\r\nstemness, plasticity and mechanisms of therapy resistance in cancer."^^ . "2025" . . . . . . . "Katherine Alexandra"^^ . "Kelly"^^ . "Katherine Alexandra Kelly"^^ . . . . . . "Acute Myeloid Leukemia with deletion 5q: an epigenetic perspective (PDF)"^^ . . . "PhDThesis_Katherine_Kelly.pdf"^^ . . . 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