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

Nature Medicine volume 13, pages 730–735 (2007)Cite this article

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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Figure 1: Null mutation of both Nr4a3 and Nr4a1 result in rapidly lethal myeloid leukemia.
Figure 2: Tissue infiltration of myeloid cells is associated with decreased lymphopoiesis.
Figure 3: Increased myeloid progenitors in Nr4a3−/−Nr4a1−/− mice.
Figure 4: Increased proliferation and survival of myeloid cells from bone marrow is associated with downregulation of the expression of the TNF receptor ligands JunB and c-Jun.

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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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Author notes

  1. Shannon E Mullican and Shuo Zhang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, 77030, Texas, USA

    Shannon E Mullican, Shuo Zhang & Orla M Conneely

  2. Department of Stem Cell Transplantation and Cellular Therapy, Section of Molecular Hematology and Therapy, University of Texas M.D. Anderson Cancer Center, Houston, 77030, Texas, USA

    Marina Konopleva, Vivian Ruvolo & Michael Andreeff

  3. Department of Pathology, Washington University School of Medicine, St. Louis, 63110, Missouri, USA

    Jeffrey Milbrandt

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Contributions

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.

Corresponding author

Correspondence to Orla M Conneely.

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The authors declare no competing financial interests.

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)

Supplementary Method (PDF 57 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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