Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Wenzl, K.
The role of the tumor suppressor genes TNFAIP3 and NR4A1 in the pathogenesis of hematological malignancies
Doktoratsstudium der Medizinischen Wissenschaft; Humanmedizin; [ Dissertation ] Graz Medical University; 2015. pp. 78
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Deutsch Alexander
- Neumeister Peter
- Prochazka Katharina
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- Abstract:
- Tumor suppressor genes are a large group of genes, which play a critical role in cell cycle, apoptosis and progression of disease. The loss of either one or both alleles can lead to malignant transformation of cells and cancer. Over the last few years scientists have shown particular interest in A20 –a negative regulator of NF-¿B activation – known to function as tumor suppressor in lymphoid malignancies. A newly identified tumor suppressor in hematologic neoplasm is NR4A1, which acts together with NR4A3 in acute myeloid leukemia and, as recently described by our group in aggressive lymphoma. The aim of this thesis was to investigate the role of A20 and NR4A1 in lymphomagenesis. Therefore, we tested 15 different types of lymphoid malignancies for the occurrence of A20 gene polymorphism rs143002189 and explored the function of NR4A1 in Myc-driven lymphomagenesis in vivo. We found the rs143002189 of germline origin with a significant higher incidence in diffuse large B-cell lymphoma compared to non-neoplastic controls and other lymphoma types. Further in silico investigations of the occurrence of the rs143002189 polymorphism on A20 protein structure predicted to alter the functional properties of the protein suggesting that the rs143002189 might contribute to lymphomagenesis. Furthermore, we could show for the first time that the loss of NR4A1 accelerated Myc driven lymphomagenesis. Additionally, the loss of NR4A1 favors infiltration by malignant B-cells in bone marrow and spleen. We could also show that B-cells lacking NR4A1 have a better in vitro survival caused by a higher proliferation. Western blot analysis revealed that the oncogenes MDM2 and Bcl-xL are both overexpressed in tumors without NR4A1. Taken together our findings we could demonstrate that A20 and NR4A1 both significantly contribute to lymphomagenesis. However, further studies in order to fully understand their functions are necessary.