NR4A1-mediated apoptosis suppresses lymphomagenesis and is associated with a favorable cancer-specific survival in patients with aggressive B-cell lymphomas

Abstract

Key Points• NR4A1 is downregulated in aggressive B-cell lymphoma.• Its overexpression causes apoptosis in lymphoma cells and suppresses lymphoma formation in vivo.NR4A1 (Nur77) and NR4A3 (Nor-1) function as tumor suppressor genes as demonstrated by the rapid development of acute myeloid leukemia in the NR4A1 and NR4A3 knockout mouse. The aim of our study was to investigate NR4A1 and NR4A3 expression and function in lymphoid malignancies. We found a vastly reduced expression of NR4A1 and NR4A3 in chronic lymphocytic B-cell leukemia (71%), in follicular lymphoma (FL, 70%), and in diffuse large B-cell lymphoma (DLBCL, 74%). In aggressive lymphomas (DLBCL and FL grade 3), low NR4A1 expression was significantly associated with a non-germinal center B-cell subtype and with poor overall survival. To investigate the function of NR4A1 in lymphomas, we overexpressed NR4A1 in several lymphoma cell lines. Overexpression of NR4A1 led to a higher proportion of lymphoma cells undergoing apoptosis. To test the tumor suppressor function of NR4A1 in vivo, the stable lentiviral-transduced SuDHL4 lymphoma cell line harboring an inducible NR4A1 construct was further investigated in xenografts. Induction of NR4A1 abrogated tumor growth in the NSG mice, in contrast to vector controls, which formed massive tumors. Our data suggest that NR4A1 has proapoptotic functions in aggressive lymphoma cells and define NR4A1 as a novel gene with tumor suppressor properties involved in lymphomagenesis. (Blood. 2014;123(15):2367-2377

Dual Inhibition of EZH2 and EZH1 Sensitizes PRC2-Dependent Tumors to Proteasome Inhibition

“…Of note, reduction of Nr4a1/3 gene expression leads to development of myelodysplastic and myeloproliferative diseases (MDS/MPN) (41), whereas targeted deletion of both genes induces lethal acute myeloid leukemia in mice (42). A recent study showed that overexpression of NR4A1 induced massive apoptotic cell death of aggressive lymphoma cell lines (43). In multiple myeloma, NR4A1-mimicking peptide induced Bcl-B–dependent apoptosis in multiple myeloma cells (34).…”

The NR4A nuclear receptors as potential targets for anti-aging interventions

“…Moreover, the reexpression of NR4A1 and NR4A3 suppresses growth and survival of human acute myeloid leukemia cells [64]. However, in other cancers from different origins such as melanoma, pancreas, breast and colon cancer, both pro and antitumor properties of NR4A receptors have been described [65][66][67][68][69]. In fact, NR4A receptors are sensors of cellular environment that participate in cell fate decision balancing between cell death and survival.…”

Universal attenuators and their interactions with feedback loops in gene regulatory networks

“…These genes are therefore likely to be encountered in relatively long LRCs, and hence conceivably have very limited RE. Notably, all of these genes have been shown to have an important role in the survival of leukaemia cells ( NFE2 (42), POLR3A (43), JunD (44), Myc (45), GATA2 (46), NR4A1 (47), IRF3 (48), IRF1 (39–41)) suggesting that cancer cells may be dynamically controlling the variation of these genes.…”