PhD thesis – Magdalena Julia Dabrowska, 12 September 2012
On Wednesday 12 September 2012, MSc (molecular biology / human biology) Magdalena Julia Dabrowska, Department of Haematology, defended her PhD thesis with the title: ”Identification and Characterization of New Genes Important for T-Cell Lymphoblastic Lymphoma Development”
T-cell lymphoblastic lymphomas (T-LBLs) are rare, but clinically very aggressive tumors. Patients with T-LBL have limited treatment options and poor prognosis. The low incidence of T-LBL is a major obstacle in studies of T-LBL biology, therefore the chromosomal abnormalities that lead to development of the disease are poorly characterized. Human T-LBLs are phenotypically and histopathologically comparable to murine T-LBLs, making the mouse lymphoma model an ideal system to study the disease in an environment similar to that in humans. When newborn mice of the NMRI inbred strain are inoculated with the SL3-3 murine leukemia virus (MLV), they develop various hematopoietic malignancies dependent on the virus mutant used, including T-LBLs.
The oncogenic properties of SL3-3 are caused by integration of the viral genome into the host genome, and deregulation of nearby cellular genes – a process defined as insertional mutagenesis. Identification of the resulting integration sites is therefore a powerful method in the identification of genes contributing to development of murine and possibly also human hematopoietic malignancies.
The main aim of the study was to identify deregulated genes and pathways in murine T-LBLs. To achieve this, thymus, spleen and lymph node tumors, induced by various SL3-3 mutants, were screened for integration sites and analysed by PCR, qPCR, microarray based gene expression profiling (GEP) and immunoblotting (western blot).
The transcriptional repressor and oncogene, growth factor independence 1 (Gfi1) was identified as the most frequently targeted gene in SL3-3 induced tumors and was activated by all SL3-3 insertions in the Gfi1 locus. We show that Gfi1 is alternatively spliced in murine T-LBLs from thymus, spleen and lymph node, and that the GFI1 protein translocates from the cytoplasm to the nucleus in both murine and human T-LBLs and lymphoid cell lines. Our results indicate that deregulated GFI1 expression is a significant hallmark in both murine and human T-LBL. GEP on murine T-LBL tumors from thymus and spleen confirmed upregulation of Gfi1, as well as increase in expression of genes involved in S phase initiation of the cell cycle, including the minichromosome maintenance (Mcm) – origin recognition (Orc) pathway.
The assessment committee consists of:
- Associate Professor Jan Alsner (chairman)
Department of Experimental Clinical Oncology, Aarhus University Hospital
- Professor Bodil Norrild
Faculty of Health and Medical Sciences, Department of Cellular and Molecular Medicine, University of Copenhagen
- Carol Stocking, PhD
AG Molecular Pathology, Heinrich-Pette-Institute, Leibniz Institute for Virology
- Associate professor Karen Dybkær
Department of Haematology, Medical Center Aalborg Hospital Science and Innovation Center, Aalborg Hospital
- Professor Finn Skou Pedersen
Department of Molecular Biology and Genetics, Aarhus University
- 12 September 2012, at 13.00 p.m.
- Auditorium 6, Room 347 (Biokemi 6) in building 1170, Aarhus University, Ole Worms Alle, 8000 Aarhus C.