title: Reduced NR4A gene dosage leads to mixed myelodysplastic/myeloproliferative neoplasms in mice.
abstract: The NR4A subfamily of nuclear receptors (NR4A1, NR4A2, and NR4A3) function as transcription factors that transduce diverse extracellular signals into altered gene transcription to coordinate apoptosis, proliferation, cell cycle arrest, and DNA repair. We previously discovered that 2 of these receptors, NR4A1 and NR4A3, are potent tumor suppressors of acute myeloid leukemia (AML); they are silenced in human AML, and abrogation of both genes in mice leads to rapid postnatal development of AML. Reduced expression of NR4As is also a common feature of myelodysplastic syndromes (MDSs). Here we show that reduced gene dosage of NR4A1 and NR4A3 in hypoallelic (NR4A1(+/-)NR4A3(-/-) or NR4A1(-/-)NR4A3(+/-)) mice below a critical threshold leads to a chronic myeloid malignancy that closely recapitulates the pathologic features of mixed myelodysplastic/myeloproliferative neoplasms (MDS/MPNs) with progression to AML in rare cases. Enhanced proliferation and excessive apoptosis of hematopoietic stem cells and myeloid progenitors, together with elevated DNA damage, contribute to MDS/MPN disease. We identify the myeloid tumor suppressor genes Egr1 and JunB and the DNA damage checkpoint kinase, polo-like kinase 2 (Plk2) as deregulated genes whose disrupted signaling probably contributes to MDS/MPN. These mice provide a novel model to elucidate the molecular pathogenesis of MDS/MPN and for therapeutic evaluation.
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Ramirez-Herrick
authors.forename: Shannon E
authors.initials: SE
authors.lastname: Mullican
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Sheehan
authors.forename: Orla M
authors.initials: OM
authors.lastname: Conneely
mesh_terms: D000483:Alleles; D000818:Animals; D017209:Apoptosis; D002451:Cell Compartmentation; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics*; D018450:Disease Progression; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D018628:Gene Dosage / Q000235:genetics*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000473:pathology; D023461:Myeloid Progenitor Cells / Q000473:pathology; D009196:Myeloproliferative Disorders / Q000235:genetics* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics*; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics*; D010641:Phenotype; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011987:Receptors, Steroid / Q000235:genetics*; D011988:Receptors, Thyroid Hormone / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D009419:Nerve Tissue Proteins; C539818:Nr4a1 protein, mouse; C490411:Nr4a3 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; C444640:serum-inducible kinase