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

Ichim, Christine V.; Dervovic, Dzana D.; Chan, Lap Shu Alan; Robertson, Claire J.; Chesney, Alden; Reis, Marciano D.; Wells, Richard A.

doi:10.1186/s40364-018-0149-4

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

Journal Article · 06 December 2018 · Biomarker Research

DOI: https://doi.org/10.1186/s40364-018-0149-4 · OSTI ID:1627060

^[1]; Dervovic, Dzana D. ^[2]; Chan, Lap Shu Alan ^[3]; Robertson, Claire J. ^[4]; Chesney, Alden ^[5]; Reis, Marciano D. ^[6]; Wells, Richard A. ^[7]

Nuclear Exploration Inc., Palo Alto, CA (United States); Univ. of Toronto, ON (Canada). Sunnybrook Research Inst. Dept. of Medical Biophysics; Sunnybrook Research Inst., Toronto, ON (Canada). Biological Sciences; DOE/OSTI
Sunnybrook Research Inst., Toronto, ON (Canada). Biological Sciences; Univ. of Toronto, ON (Canada). Dept. of Immunology
Univ. of Toronto, ON (Canada). Sunnybrook Research Inst. Dept. of Medical Biophysics; Sunnybrook Research Inst., Toronto, ON (Canada). Biological Sciences
Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States). Materials Engineering Division
Virginia Commonwealth Univ., Richmond, VA (United States). Dept. of Pathology
Univ. Health Network, Toronto, ON (Canada). Dept. of Lab. Hematology
Univ. of Toronto, ON (Canada). Sunnybrook Research Inst. Dept. of Medical Biophysics; Sunnybrook Research Inst., Toronto, ON (Canada). Biological Sciences; Virginia Commonwealth Univ., Richmond, VA (United States). Dept. of Pathology; Univ. of Toronto, ON (Canada). Dept. of Medicine; Toronto Sunnybrook Regional Cancer Centre, Toronto, ON (Canada). Myelodysplastic Syndromes Program. Dept. of Medical Oncology

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 EAR2-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.

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Research Organization:: Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)

Sponsoring Organization:: HSC Foundation; J. Douglas Crashley, Canadian Institutes of Health Research (CIHR); USDOE Office of Science (SC)

Grant/Contract Number:: AC52-07NA27344

OSTI ID:: 1627060

Journal Information:: Biomarker Research, Journal Name: Biomarker Research Journal Issue: 1 Vol. 6; ISSN 2050-7771

Publisher:: BioMed CentralCopyright Statement

Country of Publication:: United States

Language:: English

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Abnormal localization of immature precursors (ALIP) in the bone marrow of myelodysplastic syndromes: Current state of knowledge and future directions Mangi, M. H.; Salisbury, J. R.; Mufti, G. J. Leukemia Research, Vol. 15, Issue 7 https://doi.org/10.1016/0145-2126(91)90032-o	journal	January 1991
The orphan nuclear receptor EAR2 is overexpressed in colorectal cancer and it regulates survivability of colon cancer cells Li, Xue-bing; Jiao, Shi; Sun, Heng Cancer Letters, Vol. 309, Issue 2 https://doi.org/10.1016/j.canlet.2011.05.025	journal	October 2011
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Negative regulation of granulocytic differentiation in the myeloid precursor cell line 32Dcl3 by ear-2, a mammalian homolog of Drosophila seven-up, and a chimeric leukemogenic gene, AML1/ETO(MTG8) Ahn, M. -Y.; Huang, G.; Bae, S. -C. Proceedings of the National Academy of Sciences, Vol. 95, Issue 4 https://doi.org/10.1073/pnas.95.4.1812	journal	February 1998
Abnormal development of the locus coeruleus in Ear2(Nr2f6)-deficient mice impairs the functionality of the forebrain clock and affects nociception Warnecke, M. Genes & Development, Vol. 19, Issue 5 https://doi.org/10.1101/gad.317905	journal	March 2005
Loss of the Tumor Suppressor BAP1 Causes Myeloid Transformation Dey, A.; Seshasayee, D.; Noubade, R. Science, Vol. 337, Issue 6101 https://doi.org/10.1126/science.1221711	journal	August 2012
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EVI1 induces myelodysplastic syndrome in mice Buonamici, Silvia; Li, Donglan; Chi, Yiqing Journal of Clinical Investigation, Vol. 115, Issue 8 https://doi.org/10.1172/jci21716c1	journal	August 2005
Induction of myelodysplasia by myeloid-derived suppressor cells Chen, Xianghong; Eksioglu, Erika A.; Zhou, Junmin Journal of Clinical Investigation, Vol. 123, Issue 11 https://doi.org/10.1172/jci67580	journal	October 2013
Involvement and functional impairment of the CD34+CD38−Thy-1+ hematopoietic stem cell pool in myelodysplastic syndromes with trisomy 8 Nilsson, Lars; Åstrand-Grundström, Ingbritt; Anderson, Kristina Blood, Vol. 100, Issue 1 https://doi.org/10.1182/blood-2001-12-0188	journal	July 2002
Engraftment of NOD/SCID-β2 microglobulin null mice with multilineage neoplastic cells from patients with myelodysplastic syndrome Thanopoulou, Eleni; Cashman, Johanne; Kakagianne, Theodora Blood, Vol. 103, Issue 11 https://doi.org/10.1182/blood-2003-09-3192	journal	June 2004
Engraftment of distinct clonal MDS-derived hematopoietic precursors in NOD/SCID-β2-microglobulin-deficient mice after intramedullary transplantation of hematopoietic and stromal cells Kerbauy, Daniella M. Bahia; Lesnikov, Vladimir; Torok-Storb, Beverly Blood, Vol. 104, Issue 7 https://doi.org/10.1182/blood-2004-04-1518	journal	October 2004
NUP98-HOXD13 transgenic mice develop a highly penetrant, severe myelodysplastic syndrome that progresses to acute leukemia Lin, Ying-Wei; Slape, Christopher; Zhang, Zhenhua Blood, Vol. 106, Issue 1 https://doi.org/10.1182/blood-2004-12-4794	journal	July 2005
Myelodysplastic syndromes Nimer, Stephen D. Blood, Vol. 111, Issue 10 https://doi.org/10.1182/blood-2007-08-078139	journal	May 2008
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Engineering mouse models with myelodysplastic syndrome human candidate genes; how relevant are they? Beurlet, S.; Chomienne, C.; Padua, R. A. Haematologica, Vol. 98, Issue 1 https://doi.org/10.3324/haematol.2012.069385	journal	October 2012
NR1H3 Expression is a Prognostic Factor of Overall Survival for Patients with Muscle-Invasive Bladder Cancer Wu, Junlong; Wan, Fangning; Sheng, Haoyue Journal of Cancer, Vol. 8, Issue 5 https://doi.org/10.7150/jca.17845	journal	January 2017
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Abnormal localization of immature precursors (ALIP) in the bone marrow of myelodysplastic syndromes: Current state of knowledge and future directions Mangi, M. H.; Salisbury, J. R.; Mufti, G. J. Leukemia Research, Vol. 15, Issue 7 https://doi.org/10.1016/0145-2126(91)90032-O	journal	January 1991
NOD/SCID mice transplanted with marrow from patients with myelodysplastic syndrome (MDS) show long-term propagation of normal but not clonal human precursors Benito, Ana I.; Bryant, Eileen; Loken, Michael R. Leukemia Research, Vol. 27, Issue 5 https://doi.org/10.1016/S0145-2126(02)00221-7	journal	May 2003
The orphan nuclear receptor EAR2 is overexpressed in colorectal cancer and it regulates survivability of colon cancer cells Li, Xue-bing; Jiao, Shi; Sun, Heng Cancer Letters, Vol. 309, Issue 2 https://doi.org/10.1016/j.canlet.2011.05.025	journal	October 2011
Telomere Dysfunction Drives Aberrant Hematopoietic Differentiation and Myelodysplastic Syndrome Colla, Simona; Ong, Derrick Sek Tong; Ogoti, Yamini Cancer Cell, Vol. 27, Issue 5 https://doi.org/10.1016/j.ccell.2015.04.007	journal	May 2015
The orphan nuclear receptor Ear-2 (Nr2f6) is a novel negative regulator of T cell development Ichim, Christine V.; Dervović, Džana D.; Zúñiga-Pflücker, Juan Carlos Experimental Hematology, Vol. 42, Issue 1 https://doi.org/10.1016/j.exphem.2013.09.010	journal	January 2014
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The Nuclear Orphan Receptor NR2F6 Suppresses Lymphocyte Activation and T Helper 17-Dependent Autoimmunity Hermann-Kleiter, Natascha; Gruber, Thomas; Lutz-Nicoladoni, Christina Immunity, Vol. 29, Issue 2 https://doi.org/10.1016/j.immuni.2008.06.008	journal	August 2008
Impaired clonogenic growth of myelodysplastic bone marrow progenitors in vitro is irrelevant to their apoptotic state Michalopoulou, Sotiria; Micheva, Ilina; Kouraklis-Symeonidis, Alexandra Leukemia Research, Vol. 28, Issue 8 https://doi.org/10.1016/j.leukres.2003.12.004	journal	August 2004
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Many are called MDS cell lines: One is chosen Drexler, Hans G.; Dirks, Willy G.; MacLeod, Roderick A. F. Leukemia Research, Vol. 33, Issue 8 https://doi.org/10.1016/j.leukres.2009.03.005	journal	August 2009
Mouse models of myelodysplastic syndromes Wegrzyn, Joanna; Lam, Jeffrey C.; Karsan, Aly Leukemia Research, Vol. 35, Issue 7 https://doi.org/10.1016/j.leukres.2011.03.007	journal	July 2011
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Identification of a role for the nuclear receptor EAR-2 in the maintenance of clonogenic status within the leukemia cell hierarchy Ichim, C. V.; Atkins, H. L.; Iscove, N. N. Leukemia, Vol. 25, Issue 11 https://doi.org/10.1038/leu.2011.137	journal	June 2011
An MDS xenograft model utilizing a patient-derived cell line Rhyasen, G. W.; Wunderlich, M.; Tohyama, K. Leukemia, Vol. 28, Issue 5 https://doi.org/10.1038/leu.2013.372	journal	December 2013
Role of nucleophosmin in embryonic development and tumorigenesis Grisendi, Silvia; Bernardi, Rosa; Rossi, Marco Nature, Vol. 437, Issue 7055 https://doi.org/10.1038/nature03915	journal	July 2005
Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia Raaijmakers, Marc H. G. P.; Mukherjee, Siddhartha; Guo, Shangqin Nature, Vol. 464, Issue 7290 https://doi.org/10.1038/nature08851	journal	March 2010
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Evaluation of apoptosis as a prognostic factor in myelodysplastic syndromes: Apoptosis as a Risk Factor in MDS Shimazaki, K.; Ohshima, K.; Suzumiya, J. British Journal of Haematology, Vol. 110, Issue 3 https://doi.org/10.1046/j.1365-2141.2000.02228.x	journal	September 2000
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Negative regulation of granulocytic differentiation in the myeloid precursor cell line 32Dcl3 by ear-2, a mammalian homolog of Drosophila seven-up, and a chimeric leukemogenic gene, AML1/ETO(MTG8) Ahn, M. -Y.; Huang, G.; Bae, S. -C. Proceedings of the National Academy of Sciences, Vol. 95, Issue 4 https://doi.org/10.1073/pnas.95.4.1812	journal	February 1998
Abnormal development of the locus coeruleus in Ear2(Nr2f6)-deficient mice impairs the functionality of the forebrain clock and affects nociception Warnecke, M. Genes & Development, Vol. 19, Issue 5 https://doi.org/10.1101/gad.317905	journal	March 2005
Loss of the Tumor Suppressor BAP1 Causes Myeloid Transformation Dey, A.; Seshasayee, D.; Noubade, R. Science, Vol. 337, Issue 6101 https://doi.org/10.1126/science.1221711	journal	August 2012
The Orphan Nuclear Receptor Ear-2 Is a Negative Coregulator for Thyroid Hormone Nuclear Receptor Function Zhu, Xu-guang; Park, Kyung Soo; Kaneshige, Masahiro Molecular and Cellular Biology, Vol. 20, Issue 7 https://doi.org/10.1128/MCB.20.7.2604-2618.2000	journal	April 2000
The Myelodysplastic Syndromes: A Matter of Life or Death Parker, Jane E.; Mufti, Ghulam J. Acta Haematologica, Vol. 111, Issue 1-2 https://doi.org/10.1159/000074488	journal	December 2003
Identification of a Nuclear Orphan Receptor (Ear2) as a Negative Regulator of Renin Gene Transcription Liu, Xuebo; Huang, Xiaodong; Sigmund, Curt D. Circulation Research, Vol. 92, Issue 9 https://doi.org/10.1161/01.RES.0000071355.82009.43	journal	May 2003
EVI1 induces myelodysplastic syndrome in mice Buonamici, Silvia; Li, Donglan; Chi, Yiqing Journal of Clinical Investigation, Vol. 114, Issue 5 https://doi.org/10.1172/JCI21716	journal	September 2004
Induction of myelodysplasia by myeloid-derived suppressor cells Chen, Xianghong; Eksioglu, Erika A.; Zhou, Junmin Journal of Clinical Investigation, Vol. 123, Issue 11 https://doi.org/10.1172/JCI67580	journal	October 2013
Myelodysplastic syndromes are induced by histone methylationâ€“altering ASXL1 mutations Inoue, Daichi; Kitaura, Jiro; Togami, Katsuhiro Journal of Clinical Investigation, Vol. 123, Issue 11 https://doi.org/10.1172/JCI70739	journal	October 2013
EVI1 induces myelodysplastic syndrome in mice Buonamici, Silvia; Li, Donglan; Chi, Yiqing Journal of Clinical Investigation, Vol. 115, Issue 8 https://doi.org/10.1172/jci21716c1	journal	August 2005
Involvement and functional impairment of the CD34+CD38−Thy-1+ hematopoietic stem cell pool in myelodysplastic syndromes with trisomy 8 Nilsson, Lars; Åstrand-Grundström, Ingbritt; Anderson, Kristina Blood, Vol. 100, Issue 1 https://doi.org/10.1182/blood-2001-12-0188	journal	July 2002
Engraftment of NOD/SCID-β2 microglobulin null mice with multilineage neoplastic cells from patients with myelodysplastic syndrome Thanopoulou, Eleni; Cashman, Johanne; Kakagianne, Theodora Blood, Vol. 103, Issue 11 https://doi.org/10.1182/blood-2003-09-3192	journal	June 2004
Engraftment of distinct clonal MDS-derived hematopoietic precursors in NOD/SCID-β2-microglobulin-deficient mice after intramedullary transplantation of hematopoietic and stromal cells Kerbauy, Daniella M. Bahia; Lesnikov, Vladimir; Torok-Storb, Beverly Blood, Vol. 104, Issue 7 https://doi.org/10.1182/blood-2004-04-1518	journal	October 2004
NUP98-HOXD13 transgenic mice develop a highly penetrant, severe myelodysplastic syndrome that progresses to acute leukemia Lin, Ying-Wei; Slape, Christopher; Zhang, Zhenhua Blood, Vol. 106, Issue 1 https://doi.org/10.1182/blood-2004-12-4794	journal	July 2005
AML1 mutations induced MDS and MDS/AML in a mouse BMT model Watanabe-Okochi, Naoko; Kitaura, Jiro; Ono, Ryoichi Blood, Vol. 111, Issue 8 https://doi.org/10.1182/blood-2007-01-068346	journal	April 2008
Myelodysplastic syndromes Nimer, Stephen D. Blood, Vol. 111, Issue 10 https://doi.org/10.1182/blood-2007-08-078139	journal	May 2008
Revisiting the case for genetically engineered mouse models in human myelodysplastic syndrome research Zhou, Ting; Kinney, Marsha C.; Scott, Linda M. Blood, Vol. 126, Issue 9 https://doi.org/10.1182/blood-2015-01-624239	journal	August 2015
Intramedullary apoptosis of hematopoietic cells in myelodysplastic syndrome patients can be massive: apoptotic cells recovered from high-density fraction of bone marrow aspirates Shetty, Vilasini; Hussaini, Seema; Broady-Robinson, LaTanya Blood, Vol. 96, Issue 4 https://doi.org/10.1182/blood.V96.4.1388	journal	August 2000
Isolation and characterization of hematopoietic progenitor/stem cells in 5q-deleted myelodysplastic syndromes: evidence for involvement at the hematopoietic stem cell level Nilsson, Lars; Åstrand-Grundström, Ingbritt; Arvidsson, Ingrid Blood, Vol. 96, Issue 6 https://doi.org/10.1182/blood.V96.6.2012.h8002012a_2012_2021	journal	September 2000
Generation of high-titer viral preparations by concentration using successive rounds of ultracentrifugation Ichim, Christine V.; Wells, Richard A. Journal of Translational Medicine, Vol. 9, Issue 1 https://doi.org/10.1186/1479-5876-9-137	journal	August 2011
Myelodysplastic Syndromes Cilloni, D. Annals of the New York Academy of Sciences, Vol. 1028, Issue 1 https://doi.org/10.1196/annals.1322.048	journal	December 2004
Research Resource: Nuclear Receptors as Transcriptome: Discriminant and Prognostic Value in Breast Cancer Muscat, George E. O.; Eriksson, Natalie A.; Byth, Karen Molecular Endocrinology, Vol. 27, Issue 2 https://doi.org/10.1210/me.2012-1265	journal	February 2013
Engineering mouse models with myelodysplastic syndrome human candidate genes; how relevant are they? Beurlet, S.; Chomienne, C.; Padua, R. A. Haematologica, Vol. 98, Issue 1 https://doi.org/10.3324/haematol.2012.069385	journal	October 2012
NR2F6 Expression Correlates with Pelvic Lymph Node Metastasis and Poor Prognosis in Early-Stage Cervical Cancer Niu, Chunhao; Sun, Xiaoying; Zhang, Weijing International Journal of Molecular Sciences, Vol. 17, Issue 10 https://doi.org/10.3390/ijms17101694	journal	October 2016
NR1H3 Expression is a Prognostic Factor of Overall Survival for Patients with Muscle-Invasive Bladder Cancer Wu, Junlong; Wan, Fangning; Sheng, Haoyue Journal of Cancer, Vol. 8, Issue 5 https://doi.org/10.7150/jca.17845	journal	January 2017

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
Bone marrow transplant
Clonogenicity
Differentiation
Hematopoiesis
Mouse model
Myelodysplastic syndrome
Nuclear receptor
Oncology
Progenitor cell
Research & Experimental Medicine
Stem cell

Additional file 1: of The orphan nuclear receptor EAR-2 (NR2F6) inhibits hematopoietic cell differentiation and induces myeloid dysplasia in vivo Ichim, Christine; Dervovic, Dzana; Chan, Lap https://doi.org/10.6084/m9.figshare.7439681 The current record is supplemented by this text	text	January 2018
Additional file 1: of The orphan nuclear receptor EAR-2 (NR2F6) inhibits hematopoietic cell differentiation and induces myeloid dysplasia in vivo Ichim, Christine; Dervovic, Dzana; Chan, Lap https://doi.org/10.6084/m9.figshare.7439681.v1 The current record is supplemented by this text	text	January 2018
Additional file 2: of The orphan nuclear receptor EAR-2 (NR2F6) inhibits hematopoietic cell differentiation and induces myeloid dysplasia in vivo Ichim, Christine; Dervovic, Dzana; Chan, Lap https://doi.org/10.6084/m9.figshare.7439693 The current record is supplemented by this text	text	January 2018
Additional file 2: of The orphan nuclear receptor EAR-2 (NR2F6) inhibits hematopoietic cell differentiation and induces myeloid dysplasia in vivo Ichim, Christine; Dervovic, Dzana; Chan, Lap https://doi.org/10.6084/m9.figshare.7439693.v1 The current record is supplemented by this text	text	January 2018
The orphan nuclear receptor EAR-2 (NR2F6) inhibits hematopoietic cell differentiation and induces myeloid dysplasia in vivo Ichim, Christine; Dervovic, Dzana; Chan, Lap https://doi.org/10.6084/m9.figshare.c.4328396 The current record is supplemented by this collection	collection	January 2018
The orphan nuclear receptor EAR-2 (NR2F6) inhibits hematopoietic cell differentiation and induces myeloid dysplasia in vivo Ichim, Christine; Dervovic, Dzana; Chan, Lap https://doi.org/10.6084/m9.figshare.c.4328396.v1 The current record is supplemented by this collection	collection	January 2018