Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Unterluggauer, J.
Investigations on the role of translation initiation factors in aggressive B-cell lymphoma
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Medical University of Graz; 2019. pp. 102
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Haybäck Johannes
- Schicho Rudolf
- Sill Heinz
- Altmetrics:
- Abstract:
- Diffuse large B-cell lymphoma (DLBCL) is an aggressive neoplasm affecting the lymphatic system. Although contemporary chemo-immunotherapy can cure a considerable fraction of DLBCL-patients, 40% still succumb to their disease. Importantly, one reason for this lies in the big heterogeneity of the malignancy, which is reflected, amongst others, by two disease-relevant subtypes. In order to help patients affected by this heterogeneous disease, there is thus a constant need for new diagnostic or prognostic markers, to be able to stratify patients risk a priori and to enable moreover new targeted therapies. Cellular protein synthesis begins with the translation initiation phase, a key control step of the whole process. The task of translation initiation, which is realized by so-called eukaryotic initiation factors (eIFs), is to assemble an elongation-competent ribosome on the protein-coding mRNA. Importantly, despite this crucial role in regular cell metabolism, eIFs have also been described to contribute to diverse neoplastic settings. Nevertheless, apart from specific eIFs having already been implicated in DLBCL pathogenesis, most eIFs have never been investigated in this malignancy. To fill this gap and to look for new markers for DLBCL pathogenesis, in this study, 16 eIFs were investigated for their potential disease-relevant role in DLBCL. For this aim, a cohort of primary (n=34) and secondary (n=22) DLBCL patient samples was analyzed for the mRNA expression levels of the investigated eIF-panel. As non-neoplastic controls, germinal center B-cell specimens, isolated from non-neoplastic tonsils (n=5), were used. Interestingly, 12 out of 16 eIFs were higher expressed in DLBCL than in non-neoplastic B-cell controls (p<0.003). Furthermore, 8 eIFs of the investigated panel showed higher mRNA expression in the more aggressive DLBCL subtype when compared to the less aggressive one (p<0.05). Subsequent investigation on the protein level confirmed overexpression of eIF1A and eIF3d in DLBCL by immunohistochemical and Western blot analysis. For EIF2B5, the mRNA data revealed not only overexpression in DLBCL, but also an association with the more aggressive DLBCL subtype, which could be both confirmed by immunohistochemical analysis (p<0.04). Interestingly, high EIF2B5 mRNA expression was moreover detected to be associated with worse patient outcome in the study cohort (p=0.005), a finding that could be confirmed in two publicly available expression data sets of DLBCL patients (n=58 and n=200, p<0.015) and also on the protein level using immunohistochemical stainings (p=0.006). Finally, multivariate analysis revealed EIF2B5 as independent prognostic factor in DLBCL (p=0.003). To sum up, the present study uncovered a heavily dysregulated translation initiation pathway in DLBCL. Especially remarkable were, however, the results for eIF2B5, which indicate possible prognostic and diagnostic utility of this eIF in DLBCL pathogenesis.