Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Bischof, M.
The role of Nr4a1 in the c-Myc driven lymphomagenesis
Humanmedizin; [ Diplomarbeit/Master Thesis (UNI) ] Graz Medical University; 2016. pp.100.
[OPEN ACCESS]
FullText
- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Deutsch Alexander
- Prochazka Katharina
- Altmetrics:
- Abstract:
- The nuclear orphan receptors Nr4a1 and Nr4a3 have been demonstrated to be cooperating tumour suppressor genes leading to the rapid development of AML in double knock-out mice. Their expression is also reduced in leukemic blasts from human AML patients. My team has already published a comprehensive study on NR4A nuclear receptor expression levels in lymphoid neoplasms that revealed a marked reduction of both NR4A1 and NR4A3 in the majority of patients with B-cell chronic lymphocytic leukaemia, follicular lymphoma and diffuse large B-cell lymphoma. Interestingly, functional characterization demonstrated that NR4A1 alone induces apoptosis of aggressive lymphoma cells in vitro and suppresses tumour growth in a xenograft model. Additionally, our recent data demonstrate that a loss of Nr4a1 accelerates Myc-induced lymphomagenesis in mice. Taken all together, our data indicate a tumour suppressive function of Nr4a1 in the development of aggressive lymphomas. The aim of this work is to investigate the underlying mechanisms of Nr4a1-mediated tumour suppression in the development of aggressive lymphomas in vivo. In detail, I characterized the effect of Nr4a1-loss on pro- (Bim and p19-Mdm2-p53 axis) and anti-apoptotic genes (Bcl-2, Mcl-1 and Bcl-xl), which have to be inactivated or overexpressed for malignant transformation, in Myc-driven lymphomagenesis by using the EµMyc mouse model. Furthermore, expression analysis was performed to determine Nr4a1 and Nr4a3 expression in EµMyc Nr4a1-/- and EµMyc Nr4a1+/+ derived tumours and I investigated genetic programs which might be regulated by Nr4a1 in aggressive B-cell lymphomas. By Western blot analysis I demonstrated that Mdm2 and Bim were significantly overexpressed in the EµMyc Nr4a1-/- mouse tumours compared to EµMyc Nr4a1+/+ mice. Additionally, I observed a reduced cleavage of Parp as an apoptotic marker in the EµMyc Nr4a1-/- mouse tumours. It was shown, that EµMyc Nr4a1+/+ mouse tumours expressed Nr4a1 7-fold higher compared to the EµMyc Nr4a1-/- mouse tumours on mRNA levels. Comparing the EµMyc Nr4a1+/+ mouse tumours to the non-neoplastic control a 6-fold higher Nr4a1 mRNA-expression could be demonstrated. EµMyc Nr4a1-/- derived mouse tumours were shown to have a 60-fold lower Nr4a1-expression compared to a non-neoplastic control. EµMyc Nr4a1-/- mouse tumours were revealed to have a 4.6-fold higher expression of Nr4a3 compared to the EµMyc Nr4a1+/+ mice Thus, this project provides new insights into the molecular mechanisms by which Nr4a1 impacts the development of malignant lymphomas and normal B-cells.