Abrogation of nuclear receptors Nr4a3 andNr4a1 leads to development of acute myeloid leukemia

Abstract

Nur77 (NR4A1) and Nor-1 (NR4A3) are highly homologous orphan nuclear receptors that regulate the transcription of overlapping target genes. The transcriptional activity of both proteins is regulated in a ligand-independent manner by cell- and stimulus-specific gene induction and protein phosphorylation. Nor-1 and Nur77 have been implicated in a variety of cellular processes, including the transduction of hormonal, inflammatory, mitogenic, apoptotic and differentiative signals. Cellular responses to these proteins suggest that they may function as homeostatic regulators of proliferation, apoptosis and differentiation, and thus may regulate cellular susceptibility to tumorigenesis. Their physiological functions, however, remain poorly understood. Here we describe a previously unsuspected function of Nor-1 and Nur77-as critical tumor suppressors of myeloid leukemogenesis. The abrogation of these proteins in mice led to rapidly lethal acute myeloid leukemia (AML), involving abnormal expansion of hematopoietic stem cells (HSCs) and myeloid progenitors, decreased expression of the AP-1 transcription factors JunB and c-Jun and defective extrinsic apoptotic (Fas-L and TRAIL) signaling. We found that downregulation of NR4A3 ( NOR-1 ) and NR4A1 ( NUR77 ) was a common feature in leukemic blasts from human AML patients, irrespective of karyotype. Thus Nor-1 and Nur77 may provide potential targets for therapeutic intervention in AML.

MEF2C is activated by multiple mechanisms in a subset of T-acute lymphoblastic leukemia cell lines

“…Since BCL2 has been shown to mediate survival of thymocytes, 67,68 ectopic expression of NKX2-5/ MEF2C may promote leukemogenesis by inhibiting apoptosis. Accordingly, in acute myeloid leukemia both MEF2C 69 and NR4A1 70 have been identified as an oncogene and tumor suppressor gene, respectively, supporting their leukemic potential.…”

The hematopoietic stem cell in chronic phase CML is characterized by a transcriptional profile resembling normal myeloid progenitor cells and reflecting loss of quiescence

“…Among them were the activating protein-1 family member c-fos and the nuclear receptor subfamily 4A members 2 and 3 (NR4A2 and A3), kruppel-like factor family members 2 and 11, C/EBP-b and myeloid zink finger 1 (MZF1). As NR4A3 and NR4A1 have recently been identified as potential upstream regulators of c-Jun and JunB in a murine AML model, 32 we performed qRT-PCR to examine the expression levels of NR4A1 and to confirm downregulation of NR4A3. We detected a significant downregulation of NR4A1 and NR4A3 in HSC of CML patients by RT-PCR (Supplementary Figure 2).…”

Nuclear receptor NR4A1 promotes breast cancer invasion and metastasis by activating TGF-β signalling

“…It is a transcription factor and as an early response gene, it can be induced by many stimuli including serum, inflammatory factors, growth factors and stress in different cell types and organs 11 . NR4A1 was considered as a strong tumour suppressor because of its involvement in growth inhibition and induction of apoptosis [12][13][14][15] . Nevertheless, NR4A1 was also reported to be highly expressed in colon and pancreatic tumours.…”