Genetic and epigenetic characterization of pediatric high hyperdiploid acute lymphoblastic leukemia

Research output: ThesisDoctoral Thesis (compilation)

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 disorders with acquired or constitutional numerical chromosome anomalies. In article III we concluded that structural changes were significantly more common in relapse HeH samples than in diagnostic ones and that no single, recurrent aberration could be directly linked to relapse. In addition, the triple trisomies +4, +10, and +17, associated with low-risk ALL, were detected in two-thirds of cases that subsequently relapsed, thus questioning the favorable impact of these trisomies. The genetic differences between diagnostic and relapse samples suggest the presence of an ancestral HeH clone in the vast majority of patients, with strucutral changes and mutations being secondary to the HeH pattern.

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Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medical Genetics

Keywords

  • high hyperdiploid ALL, children, chromosome aberration, methylation profiling, array CGH, relapse, SNP array, clonal relationship, dup(1q)
Original languageEnglish
QualificationDoctor
Awarding Institution
Supervisors/Assistant supervisor
Award date2009 Nov 27
Publisher
  • Lund University, Faculty of Medicine
Print ISBNs978-91-86443-01-6
Publication statusPublished - 2009
Publication categoryResearch

Bibliographic note

Defence details Date: 2009-11-27 Time: 10:00 Place: Föreläsningssal 1 C-block, Universitetssjukhuset i Lund External reviewer(s) Name: Kearney, Lyndal Title: Dr Affiliation: The Institute of Cancer Research, University of London Sutton, UK ---

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