Genetic and epigenetic characterization of pediatric high hyperdiploid acute lymphoblastic leukemia
type: CreativeWork
description: The aim of this thesis was to analyze the genetic and epigenetic characteristics of pediatric high hyperdiploid acute lymphoblastic leukemia (HeH ALL), the most common type of childhood malignancy. The three original articles presented in this thesis have addressed three major questions regarding HeH ALL: what are the genetic characteristics of the most common structural abnormality – dup(1q)? Are aberrant methylation patterns involved in leukemogenesis? How do diagnostic and relapse samples relate to each other genetically? In article I we found that the proximal breakpoints of dup(1q)-positive Burkitt lymphomas (BL) and pediatric HeH ALLs cluster close to the centromere, suggesting this region to be breakprone, and that five genes on 1q were significantly overexpressed and thus potentially pathogenetically important. In addition, the satellite II domain was not hypomethylated in either disorder, ruling out that decondensation of pericentric heterochromatin, due to hypomethylation of satellite II sequences, is the mechanism behind dup(1q) in BL and pediatric HeH ALL. In article II unsupervised cluster and principal component analyses of BAC array chromosome-wide methylome profiles accurately subgrouped the t(12;21) and HeH ALL subtypes, demonstrating that they are characterized by subtype specific methylomes. Analysis of promoter-specific CpG islands demonstrated that several B-cell- and neoplasia-associated genes were hypermethylated and underexpressed. Methylation hotspots were associated with chromosome bands predicted to harbor imprinted genes, suggesting that regions rich in imprinted genes could be associated with aberrant methylation in t(12;21)-positive and HeH ALLs. Moreover, we demonstrated that the tri-/tetrasomic chromosomes in HeH ALLs were less methylated than their disomic counterparts. Decreased methylation of gained chromosomes is a previously unknown phenomenon that may have ramifications not only for the pathogenesis of HeH ALL but also for other…
abstract: The aim of this thesis was to analyze the genetic and epigenetic characteristics of pediatric high hyperdiploid acute lymphoblastic leukemia (HeH ALL), the most common type of childhood malignancy. The three original articles presented in this thesis have addressed three major questions regarding HeH ALL: what are the genetic characteristics of the most common structural abnormality – dup(1q)? Are aberrant methylation patterns involved in leukemogenesis? How do diagnostic and relapse samples relate to each other genetically? In article I we found that the proximal breakpoints of dup(1q)-positive Burkitt lymphomas (BL) and pediatric HeH ALLs cluster close to the centromere, suggesting this region to be breakprone, and that five genes on 1q were significantly overexpressed and thus potentially pathogenetically important. In addition, the satellite II domain was not hypomethylated in either disorder, ruling out that decondensation of pericentric heterochromatin, due to hypomethylation of satellite II sequences, is the mechanism behind dup(1q) in BL and pediatric HeH ALL. In article II unsupervised cluster and principal component analyses of BAC array chromosome-wide methylome profiles accurately subgrouped the t(12;21) and HeH ALL subtypes, demonstrating that they are characterized by subtype specific methylomes. Analysis of promoter-specific CpG islands demonstrated that several B-cell- and neoplasia-associated genes were hypermethylated and underexpressed. Methylation hotspots were associated with chromosome bands predicted to harbor imprinted genes, suggesting that regions rich in imprinted genes could be associated with aberrant methylation in t(12;21)-positive and HeH ALLs. Moreover, we demonstrated that the tri-/tetrasomic chromosomes in HeH ALLs were less methylated than their disomic counterparts. Decreased methylation of gained chromosomes is a previously unknown phenomenon that may have ramifications not only for the pathogenesis of HeH ALL but also for other…
author: Davidsson, Josef
language: eng
keywords: Medical Genetics and Genomics (including Gene Therapy), high hyperdiploid ALL, children, chromosome aberration, methylation profiling, array CGH, relapse, SNP array, clonal relationship, dup(1q)
date published: 2009
date modified: 2026-07-24T03:00:02Z
provider: University of Lund
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: Lund University, Faculty of Medicine