Nur77 (NR4A1) and Nor-1 (NR4A3) are highly homologous orphan nuclear receptors1,2 that regulate the transcription of overlapping target genes2,3. The transcriptional activity of both proteins is regulated in a ligand-independent manner by cell- and stimulus-specific gene induction and protein phosphorylation4,5. Nor-1 and Nur77 have been implicated in a variety of cellular processes, including the transduction of hormonal, inflammatory, mitogenic, apoptotic and differentiative signals4,6,7. 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.
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We thank J. Yang for technical assistance. This work was funded by the US National Institutes of Health (grant CA111411; Atlas grant U19DK62434 to O.M.C. and DAMD17-01-1-0141 to S.E.M.; and grants PO1CA55164 and CA16672 to M.A.) and by the Paul and Mary Haas Chair of Genetics at the University of Texas M.D. Anderson Cancer Center (to M.A.).
The authors declare no competing financial interests.
Genotype analysis of Nor-1−/−Nur77−/− mice. (PDF 106 kb)
Disrupted lymphoid tissues and perivascular infiltrates in non-hematopoietic tissues in Nor-1−/−Nur77−/− mice. (PDF 131 kb)
Decreased erythroid cells in Nor-1−/−Nur77−/− mice. (PDF 297 kb)
The myeloid leukemia in Nor-1−/−Nur77−/− mice was transplantable to sublethally irradiated wild type recipient mice. (PDF 158 kb)
Peripheral blood analysis of Nr4a3−/−Nr4a1−/− mice at 2–3 weeks of age. (PDF 70 kb)
AML patient samples. (PDF 13 kb)
Defining Criteria: Acute Myeloid Leukemia. (PDF 18 kb)
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