Graduation Year

2009

Document Type

Dissertation

Degree

Ph.D.

Degree Granting Department

Molecular Medicine

Major Professor

Peter Medveczky, M.D.

Keywords

Mitochondrial DNA, AIDS-related lymphomas, Oncogenic transformation, Leukemogenesis, Mitochondria

Abstract

Despite recent advances in the understanding of the molecular bases of hematological malignancies, the specific mechanisms on how they originate and why some subtypes are more prevalent than others still remain to be elucidated. These two important aspects have been even more difficult to analyze when dealing with individuals under immune suppression because other factors must be considered. Questions still remain as to why individuals with AIDS tend to develop lymphoproliferative disorders differently from those observed in individuals under iatrogenic immunosuppressive therapy. Most of lymphomas occurring in transplant recipients are B-cell neoplasias typically associated with Epstein-Barr virus (EBV) infection. In contrast, only about 50% of lymphomas of patients with AIDS are associated with lymphotrophic herpesviruses such as EBV and Kaposi's sarcoma-associated herpesvirus (KSHV).

No known infectious agent has been detected in the remaining 50% of AIDS-associated lymphomas, suggesting the involvement of novel viruses or unique molecular mechanisms. Since most oncogenic viruses persist as episomal circular viral genomes in the nuclei of tumor cells, we developed a method to visualize and identify covalently closed circular DNA (cccDNA) in lymphoma samples. Although this study revealed no novel viruses, we identified concatemers of the mitochondrial genome in all lymphoma samples tested. We further studied in detail one AIDS-associated lymphoma (denominated EL) whose mitochondrial DNA primarily consisted of tandem head-to-tail genome duplications. Insertion of cytosine residues was noted in the EL mitochondrial genome sequence near the origin of replication. EL cells responded weakly to Fas-apoptotic stimulus, displayed reduced mitochondrial activity and mass, and produced higher levels of reactive oxygen species (ROS) than control cells.

Screening of several other AIDS-associated lymphomas and established lymphoma cell lines revealed a different kind of mitochondrial genome concatemers consisting of interlinks of DNA monomer molecules. Concatemers were not detected in normal T-lymphocytes suggesting an association with neoplastic transformation. This dissertation describes the two distinct types of mitochondrial genome concatemers identified in transformed lymphoid cells and presents a detailed analysis of their structure and implications in cellular homeostasis.

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