Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Fechter, K.
INVESTIGATING THE ROLE OF NR4A1 IN AGGRESSIVE LYMPHOMAS
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2019. pp. 161
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Deutsch Alexander
- Neumeister Peter
- Prokesch Andreas
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- Abstract:
- The nuclear orphan receptor NR4A1 has been described to possess tumor suppressive functions through pro-apoptotic genomic and non-genomic effects in aggressive lymphomas. In the first part of this project, we aimed to immunohistochemically characterize the clinico-pathological relevance of NR4A1 protein expression patterns in a cohort of 60 diffuse large B cell lymphoma (DLBCL) patients and non-neoplastic lymph nodes. We observed that high cytoplasmic NR4A1 was significantly associated with favorable cancer-specific survival, the germinal center B cell-like subtype and cleaved caspase 3. Complementary, functional profiling using gene set enrichment of Reactome pathways based on a publicly available microarray data was applied to determine pathways potentially implicated in cytoplasmic localization of NR4A1 and validated by means of semi quantitative real-time PCR. The pathway analysis revealed changes in the ERK1/2 pathway, and this was corroborated by the finding that high cytoplasmic NR4A1 was associated with higher expression of ERK1/2 targets in our cohort. In the second part of this project, the effects of Nr4a1 loss on B cell lymphoma development were determined in a mouse model of Myc-driven lymphomagenesis. Therefore, first the EµMyc mouse was crossed with the Nr4a1-/- mouse. The generated mouse cohorts comprising of EµMyc Nr4a1+/+, EµMyc Nr4a1-/- and EµMyc Nr4a1 +/- mice were compared with respect to tumor formation and survival and results demonstrated accelerated tumor formation and reduced survival upon loss of Nr4a1. Moreover, investigation of bone marrow and spleen of mice at the premalignant stage revealed defects in apoptotic potential. RNASeq of tumors from EµMyc Nr4a1-/- mice and EµMyc Nr4a1+/+ mice showed that genes involved in immune function and/or immune regulation were induced by Nr4a1 loss. Hence, tumor cells of both mouse cohorts were transplanted into C57/Bl6 and immunocompromised Fox Chase Scid Beige recipients. Results from the transplantation of EµMyc Nr4a1-/- derived tumors clearly demonstrated an upregulation of immunoregulatory molecules upon loss of Nr4a1 only in immunocompetent mice. Furthermore, transplantation of the same tumors led to an enhanced dissemination potential to the bone marrow of immunocompetent but not immunodeficient mice. These data indicate that high cytoplasmic NR4A1 is associated with a favorable lymphoma-specific survival in DLBCL patients by induction of apoptosis. Likewise, in a lymphoma mouse model, it functions as a tumor suppressor by transregulating immunemodulatory genes. Collectively, these studies underpin the importance of NR4A1 as potential prognostic marker for risk assessment in aggressive lymphomas.