The orphan nuclear receptor EAR-2 (NR2F6) inhibits hematopoietic cell differentiation and induces myeloid dysplasia in vivo.

Autor: Ichim CV; Nuclear Exploration Inc., Palo Alto, California 94301 USA.; 3Department of Medical Biophysics, University of Toronto, Sunnybrook Research Institute, Toronto, ON M4N 3M5 Canada.; 4Biological Sciences, Sunnybrook Research Institute, Toronto, ON M4N 3M5 Canada., Dervovic DD; 4Biological Sciences, Sunnybrook Research Institute, Toronto, ON M4N 3M5 Canada.; 5Department of Immunology, University of Toronto, Toronto, ON M5S 1A8 Canada., Chan LSA; 3Department of Medical Biophysics, University of Toronto, Sunnybrook Research Institute, Toronto, ON M4N 3M5 Canada.; 4Biological Sciences, Sunnybrook Research Institute, Toronto, ON M4N 3M5 Canada., Robertson CJ; 1Materials Engineering Division, Lawrence Livermore National Lab, 7000 East Ave, Livermore, CA USA., Chesney A; 6VCU Medical Centre, Department of Pathology, Richmond, VA 23298 USA., Reis MD; 9Department of Laboratory Hematology, University Health Network, Toronto, ON M5G 2C4 Canada., Wells RA; 3Department of Medical Biophysics, University of Toronto, Sunnybrook Research Institute, Toronto, ON M4N 3M5 Canada.; 4Biological Sciences, Sunnybrook Research Institute, Toronto, ON M4N 3M5 Canada.; 6VCU Medical Centre, Department of Pathology, Richmond, VA 23298 USA.; 7Department of Medicine, University of Toronto, Toronto, ON M5G 2C4 Canada.; 8Department of Medical Oncology, Myelodysplastic Syndromes Program, Toronto Sunnybrook Regional Cancer Centre, Toronto, ON M4N 3M5 Canada.
Jazyk: angličtina
Zdroj: Biomarker research [Biomark Res] 2018 Dec 07; Vol. 6, pp. 36. Date of Electronic Publication: 2018 Dec 07 (Print Publication: 2018).
DOI: 10.1186/s40364-018-0149-4
Abstrakt: Background: In patients with myelodysplastic syndrome (MDS), bone marrow cells have an increased predisposition to apoptosis, yet MDS cells outcompete normal bone marrow (BM)-- suggesting that factors regulating growth potential may be important in MDS. We previously identified v-Erb A related-2 (EAR-2, NR2F6) as a gene involved in control of growth ability.
Methods: Bone marrow obtained from C57BL/6 mice was transfected with a retrovirus containing EAR-2-IRES-GFP. Ex vivo transduced cells were flow sorted. In some experiments cells were cultured in vitro, in other experiments cells were injected into lethally irradiated recipients, along with non-transduced bone marrow cells. Short-hairpin RNA silencing EAR-2 was also introduced into bone marrow cells cultured ex vivo.
Results: Here, we show that EAR-2 inhibits maturation of normal BM in vitro and in vivo and that EAR-2 transplant chimeras demonstrate key features of MDS. Competitive repopulation of lethally irradiated murine hosts with EAR-2-transduced BM cells resulted in increased engraftment and increased colony formation in serial replating experiments. Recipients of EAR-2-transduced grafts had hypercellular BM, erythroid dysplasia, abnormal localization of immature precursors and increased blasts; secondary transplantation resulted in acute leukemia. Animals were cytopenic, having reduced numbers of erythrocytes, monocytes and granulocytes. Suspension culture confirmed that EAR-2 inhibits granulocytic and monocytic differentiation, while knockdown induced granulocytic differentiation. We observed a reduction in the number of BFU-E and CFU-GM colonies and the size of erythroid and myeloid colonies. Serial replating of transduced hematopoietic colonies revealed extended replating potential in EAR-2-overexpressing BM, while knockdown reduced re-plating ability. EAR-2 functions by recruitment of histone deacetylases, and inhibition of differentiation in 32D cells is dependent on the DNA binding domain.
Conclusions: This data suggest that NR2F6 inhibits maturation of normal BM in vitro and in vivo and that the NR2F6 transplant chimera system demonstrates key features of MDS, and could provide a mouse model for MDS.
Competing Interests: Not applicableNot applicableCVI is a former employee of Regen BioPharma Inc. She has received research support, compensation, and owns stock in the company. The other authors have declared nothing to disclose.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Databáze: MEDLINE
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