Abstract
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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References
Milbrandt, J. Nerve growth factor induces a gene homologous to the glucocorticoid receptor gene. Neuron 1, 183–188 (1988).
Hedvat, C.V. & Irving, S.G. The isolation and characterization of MINOR, a novel mitogen-inducible nuclear orphan receptor. Mol. Endocrinol. 9, 1692–1700 (1995).
Wilson, T.E., Fahrner, T.J., Johnston, M. & Milbrandt, J. Identification of the DNA binding site for NGFI-B by genetic selection in yeast. Science 252, 1296–1300 (1991).
Hazel, T.G., Nathans, D. & Lau, L.F. A gene inducible by serum growth factors encodes a member of the steroid and thyroid hormone receptor superfamily. Proc. Natl. Acad. Sci. USA 85, 8444–8448 (1988).
Pekarsky, Y. et al. Akt phosphorylates and regulates the orphan nuclear receptor Nur77. Proc. Natl. Acad. Sci. USA 98, 3690–3694 (2001).
Davis, I.J. & Lau, L.F. Endocrine and neurogenic regulation of the orphan nuclear receptors Nur77 and Nurr-1 in the adrenal glands. Mol. Cell. Biol. 14, 3469–3483 (1994).
Pei, L., Castrillo, A., Chen, M., Hoffmann, A. & Tontonoz, P. Induction of NR4A orphan nuclear receptor expression in macrophages in response to inflammatory stimuli. J. Biol. Chem. 280, 29256–29262 (2005).
Tenen, D.G. Disruption of differentiation in human cancer: AML shows the way. Nat. Rev. Cancer 3, 89–101 (2003).
Cozzio, A. et al. Similar MLL-associated leukemias arising from self-renewing stem cells and short-lived myeloid progenitors. Genes Dev. 17, 3029–3035 (2003).
Huntly, B.J. et al. MOZ-TIF2, but not BCR-ABL, confers properties of leukemic stem cells to committed murine hematopoietic progenitors. Cancer Cell 6, 587–596 (2004).
Nucifora, G. et al. Detection of DNA rearrangements in the AML1 and ETO loci and of an AML1/ETO fusion mRNA in patients with t(8;21) acute myeloid leukemia. Blood 81, 883–888 (1993).
Ayton, P.M. & Cleary, M.L. Molecular mechanisms of leukemogenesis mediated by MLL fusion proteins. Oncogene 20, 5695–5707 (2001).
Pabst, T. et al. Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-α (C/EBPα), in acute myeloid leukemia. Nat. Genet. 27, 263–270 (2001).
Vangala, R.K. et al. The myeloid master regulator transcription factor PU.1 is inactivated by AML1-ETO in t(8;21) myeloid leukemia. Blood 101, 270–277 (2003).
Pabst, T. et al. AML1-ETO downregulates the granulocytic differentiation factor C/EBPalpha in t(8;21) myeloid leukemia. Nat. Med. 7, 444–451 (2001).
Yuan, Y. et al. AML1-ETO expression is directly involved in the development of acute myeloid leukemia in the presence of additional mutations. Proc. Natl. Acad. Sci. USA 98, 10398–10403 (2001).
Castilla, L.H. et al. Identification of genes that synergize with Cbfb-MYH11 in the pathogenesis of acute myeloid leukemia. Proc. Natl. Acad. Sci. USA 101, 4924–4929 (2004).
Rajpal, A. et al. Transcriptional activation of known and novel apoptotic pathways by Nur77 orphan steroid receptor. EMBO J. 22, 6526–6536 (2003).
Lee, J.M., Lee, K.H., Weidner, M., Osborne, B.A. & Hayward, S.D. Epstein-Barr virus EBNA2 blocks Nur77- mediated apoptosis. Proc. Natl. Acad. Sci. USA 99, 11878–11883 (2002).
Uemura, H. & Chang, C. Antisense TR3 orphan receptor can increase prostate cancer cell viability with etoposide treatment. Endocrinology 139, 2329–2334 (1998).
Martinez-Gonzalez, J., Rius, J., Castello, A., Cases-Langhoff, C. & Badimon, L. Neuron-derived orphan receptor-1 (NOR-1) modulates vascular smooth muscle cell proliferation. Circ. Res. 92, 96–103 (2003).
Lee, S.L. et al. Unimpaired thymic and peripheral T cell death in mice lacking the nuclear receptor NGFI-B (Nur77). Science 269, 532–535 (1995).
Ponnio, T., Burton, Q., Pereira, F.A., Wu, D.K. & Conneely, O.M. The nuclear receptor Nor-1 is essential for proliferation of the semicircular canals of the mouse inner ear. Mol. Cell. Biol. 22, 935–945 (2002).
Rosenbauer, F. et al. Acute myeloid leukemia induced by graded reduction of a lineage-specific transcription factor, PU.1. Nat. Genet. 36, 624–630 (2004).
Steidl, U. et al. Essential role of Jun family transcription factors in PU.1 knockdown-induced leukemic stem cells. Nat. Genet. 38, 1269–1277 (2006).
Passegue, E., Jochum, W., Schorpp-Kistner, M., Mohle-Steinlein, U. & Wagner, E.F. Chronic myeloid leukemia with increased granulocyte progenitors in mice lacking junB expression in the myeloid lineage. Cell 104, 21–32 (2001).
Insinga, A. et al. Inhibitors of histone deacetylases induce tumor-selective apoptosis through activation of the death receptor pathway. Nat. Med. 11, 71–76 (2005).
Nebbioso, A. et al. Tumor-selective action of HDAC inhibitors involves TRAIL induction in acute myeloid leukemia cells. Nat. Med. 11, 77–84 (2005).
Traver, D., Akashi, K., Weissman, I.L. & Lagasse, E. Mice defective in two apoptosis pathways in the myeloid lineage develop acute myeloblastic leukemia. Immunity 9, 47–57 (1998).
Ordentlich, P., Yan, Y., Zhou, S. & Heyman, R.A. Identification of the antineoplastic agent 6-mercaptopurine as an activator of the orphan nuclear hormone receptor Nurr1. J. Biol. Chem. 278, 24791–24799 (2003).
Acknowledgements
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.).
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S.E.M. and S.Z. designed and performed the experiments, and contributed to manuscript writing. M.K., V.R. and M.A. provided human AML samples, performed human AML analyses and edited the manuscript. J.M. provided Nr4a1−/− mice. O.M.C. designed the experiments and wrote the manuscript.
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Supplementary information
Supplementary Fig. 1
Genotype analysis of Nor-1−/−Nur77−/− mice. (PDF 106 kb)
Supplementary Fig. 2
Disrupted lymphoid tissues and perivascular infiltrates in non-hematopoietic tissues in Nor-1−/−Nur77−/− mice. (PDF 131 kb)
Supplementary Fig. 3
Decreased erythroid cells in Nor-1−/−Nur77−/− mice. (PDF 297 kb)
Supplementary Fig. 4
The myeloid leukemia in Nor-1−/−Nur77−/− mice was transplantable to sublethally irradiated wild type recipient mice. (PDF 158 kb)
Supplementary Table 1
Peripheral blood analysis of Nr4a3−/−Nr4a1−/− mice at 2–3 weeks of age. (PDF 70 kb)
Supplementary Table 2
AML patient samples. (PDF 13 kb)
Supplementary Table 3
Defining Criteria: Acute Myeloid Leukemia. (PDF 18 kb)
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Mullican, S., Zhang, S., Konopleva, M. et al. Abrogation of nuclear receptors Nr4a3 andNr4a1 leads to development of acute myeloid leukemia. Nat Med 13, 730–735 (2007). https://doi.org/10.1038/nm1579
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DOI: https://doi.org/10.1038/nm1579
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