Abstract
The nuclear orphan receptor NR4A1 functions as tumour suppressor in aggressive lymphomas by pro-apoptotic genomic and non-genomic effects. Here, we immunohistochemically studied 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 a significant association between high cytoplasmic NR4A1 and favourable cancer-specific survival and the germinal centre B cell-like subtype, respectively. Moreover, the percentage of lymphoma cells exhibiting cytoplasmic NR4A1 significantly correlated to those showing cleaved caspase 3. Complementary, functional profiling using gene set enrichment of Reactome pathways based on 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. These data indicate that high cytoplasmic NR4A1 is associated with a favourable lymphoma-specific survival and highlights the importance of NR4A1 expression patterns as potential prognostic marker for risk assessment in aggressive lymphomas.
Highlights
The nuclear orphan receptor NR4A1 functions as tumour suppressor in aggressive lymphomas by proapoptotic genomic and non-genomic effects
We previously demonstrated a significant reduction of both - NR4A1 and NR4A3 – in major B cell neoplasms like chronic lymphocytic leukaemia (CLL), follicular lymphoma (FL) and diffuse large B cell lymphoma (DLBCL) compared to normal controls[9]
As we have previously reported, total NR4A1 expression is significantly reduced in aggressive lymphoma specimens when compared to non-neoplastic germinal centre B cells (GC-B)[9]
Summary
The nuclear orphan receptor NR4A1 functions as tumour suppressor in aggressive lymphomas by proapoptotic genomic and non-genomic effects. Gene expression profiling showed that DLBCLs cluster into three different subtypes based on an expression pattern similar to the cellular origin: germinal centre B cell-like (GCB-DLBCL), activated B cell-like/ or non-germinal centre B cell-like DLBCL (ABC-DBLCL or NGCB-DLBCL) and primary mediastinal B cell lymphoma (PMBL)[3,4]. These subtypes of DLBCLs are associated with distinctly different overall survival rates after immunochemotherapy such as R-CHOP (Rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone): overall survival is favourable in patients with GCB subtype and PMBL, and inferior in those with the NGCB subtype[3]. We found significantly increased expression of genes regulated by extracellular signal-related kinase 1/2 (ERK1/2) in DLBCLs exhibiting high cytoplasmic NR4A1 content, indicating that this pathway could cause or at least contribute to the translocation and subsequent induction of apoptosis by NR4A1
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