Letter abstract
Nature Medicine 13, 730 - 735 (2007)
Published online: 21 May 2007 | doi:10.1038/nm1579
Abrogation of nuclear receptors Nr4a3 andNr4a1 leads to development of acute myeloid leukemia
Shannon E Mullican1,4, Shuo Zhang1,4, Marina Konopleva2, Vivian Ruvolo2, Michael Andreeff2, Jeffrey Milbrandt3 & Orla M Conneely1
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.
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
- Section of Molecular Hematology and Therapy, Department of Stem Cell Transplantation and Cellular Therapy, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
- Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
- These authors contributed equally to this work.
Correspondence to: Orla M Conneely1 e-mail: orlac@bcm.tmc.edu
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