title: GEP analysis validates high risk MDS and acute myeloid leukemia post MDS mice models and highlights novel dysregulated pathways.
abstract: BACKGROUND
  In spite of the recent discovery of genetic mutations in most myelodysplasic (MDS) patients, the pathophysiology of these disorders still remains poorly understood, and only few in vivo models are available to help unravel the disease.
  
  
  METHODS
  We performed global specific gene expression profiling and functional pathway analysis in purified Sca1+ cells of two MDS transgenic mouse models that mimic human high-risk MDS (HR-MDS) and acute myeloid leukemia (AML) post MDS, with NRASD12 and BCL2 transgenes under the control of different promoters MRP8NRASD12/tethBCL-2 or MRP8[NRASD12/hBCL-2], respectively.
  
  
  RESULTS
  Analysis of dysregulated genes that were unique to the diseased HR-MDS and AML post MDS mice and not their founder mice pointed first to pathways that had previously been reported in MDS patients, including DNA replication/damage/repair, cell cycle, apoptosis, immune responses, and canonical Wnt pathways, further validating these models at the gene expression level. Interestingly, pathways not previously reported in MDS were discovered. These included dysregulated genes of noncanonical Wnt pathways and energy and lipid metabolisms. These dysregulated genes were not only confirmed in a different independent set of BM and spleen Sca1+ cells from the MDS mice but also in MDS CD34+ BM patient samples.
  
  
  CONCLUSIONS
  These two MDS models may thus provide useful preclinical models to target pathways previously identified in MDS patients and to unravel novel pathways highlighted by this study.
authors.affiliation: Université Paris-Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Unité Mixte de Recherche (UMR-S) 1131, Paris, France. lguerenne@gmail.com.|Institut National de la Santé et de la Recherche Médicale (INSERM) Unité (U) 1131, Paris, France. lguerenne@gmail.com.
authors.forename: Laura
authors.initials: L
authors.lastname: Guerenne
authors.affiliation: Université Paris-Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Unité Mixte de Recherche (UMR-S) 1131, Paris, France. stephanie.beurlet@free.fr.|Institut National de la Santé et de la Recherche Médicale (INSERM) Unité (U) 1131, Paris, France. stephanie.beurlet@free.fr.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Beurlet
authors.affiliation: Department of Haematological Medicine, King's College London and Kings College Hospital, London, UK. malih100@gmail.com.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Said
authors.affiliation: Université Paris-Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Unité Mixte de Recherche (UMR-S) 1131, Paris, France. Petra.gorombei@gmail.com.|Institut National de la Santé et de la Recherche Médicale (INSERM) Unité (U) 1131, Paris, France. Petra.gorombei@gmail.com.
authors.forename: Petra
authors.initials: P
authors.lastname: Gorombei
authors.affiliation: Université Paris-Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Unité Mixte de Recherche (UMR-S) 1131, Paris, France. clp_5@hotmail.com.|Institut National de la Santé et de la Recherche Médicale (INSERM) Unité (U) 1131, Paris, France. clp_5@hotmail.com.
authors.forename: Carole
authors.initials: C
authors.lastname: Le Pogam
authors.affiliation: Université Paris-Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Unité Mixte de Recherche (UMR-S) 1131, Paris, France. fabien.guidez@inserm.fr.|Institut National de la Santé et de la Recherche Médicale (INSERM) Unité (U) 1131, Paris, France. fabien.guidez@inserm.fr.
authors.forename: Fabien
authors.initials: F
authors.lastname: Guidez
authors.affiliation: GenoSplice technology, iPEPS-ICM, Hôpital de la Pitié Salpêtrière, Paris, France. pierre.delagrange@genosplice.com.
authors.forename: Pierre
authors.initials: P
authors.lastname: de la Grange
authors.affiliation: Haematology Department, Cardiff University School of Medicine, Cardiff, UK. omidvarn@Cardiff.ac.uk.
authors.forename: Nader
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authors.lastname: Omidvar
authors.affiliation: Assistance Publique-Hôpitaux de Paris (AP-HP), Unité de Thérapie Cellulaire, Hôpital Saint Louis, Paris, France. valerie.vanneaux@sls.aphp.fr.
authors.forename: Valérie
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authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK. k.mills@qub.ac.uk.
authors.forename: Ken
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authors.lastname: Mills
authors.affiliation: Department of Haematological Medicine, King's College London and Kings College Hospital, London, UK. ghulam.mufti@kcl.ac.uk.
authors.forename: Ghulam J
authors.initials: GJ
authors.lastname: Mufti
authors.affiliation: Université Paris-Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie Hôpital Saint Louis, Paris, France. laure.sarda@inserm.fr.|Assistance Publique-Hôpitaux de Paris (AP-HP), Service de Médecine Nucléaire, Hôpital Lariboisière, Paris, France. laure.sarda@inserm.fr.
authors.forename: Laure
authors.initials: L
authors.lastname: Sarda-Mantel
authors.affiliation: Assistance Publique-Hôpitaux de Paris (AP-HP), Laboratoire d'Hématologie, Hôpital Saint Louis, Paris, France. maria-elena.noguera@sls.aphp.fr.
authors.forename: Maria Elena
authors.initials: ME
authors.lastname: Noguera
authors.affiliation: Université Paris-Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Unité Mixte de Recherche (UMR-S) 1131, Paris, France. Marika.Pla@inserm.fr.|Institut National de la Santé et de la Recherche Médicale (INSERM) Unité (U) 1131, Paris, France. Marika.Pla@inserm.fr.|Université Paris-Diderot, Sorbonne Paris Cité, Département d'Expérimentation Animale, Institut Universitaire d'Hématologie, Paris, France. Marika.Pla@inserm.fr.
authors.forename: Marika
authors.initials: M
authors.lastname: Pla
authors.affiliation: Université Paris-Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Unité Mixte de Recherche (UMR-S) 1131, Paris, France. pierre.fenaux@sls.aphp.fr.|Institut National de la Santé et de la Recherche Médicale (INSERM) Unité (U) 1131, Paris, France. pierre.fenaux@sls.aphp.fr.|Assistance Publique-Hôpitaux de Paris (AP-HP), Laboratoire d'Hématologie, Hôpital Saint Louis, Paris, France. pierre.fenaux@sls.aphp.fr.
authors.forename: Pierre
authors.initials: P
authors.lastname: Fenaux
authors.affiliation: Université Paris-Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Unité Mixte de Recherche (UMR-S) 1131, Paris, France. Rose-Ann.Padua@inserm.fr.|Institut National de la Santé et de la Recherche Médicale (INSERM) Unité (U) 1131, Paris, France. Rose-Ann.Padua@inserm.fr.|Assistance Publique-Hôpitaux de Paris (AP-HP), Laboratoire d'Hématologie, Hôpital Saint Louis, Paris, France. Rose-Ann.Padua@inserm.fr.
authors.forename: Rose Ann
authors.initials: RA
authors.lastname: Padua
authors.affiliation: Université Paris-Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Unité Mixte de Recherche (UMR-S) 1131, Paris, France. christine.chomienne@sls.aphp.fr.|Institut National de la Santé et de la Recherche Médicale (INSERM) Unité (U) 1131, Paris, France. christine.chomienne@sls.aphp.fr.|Assistance Publique-Hôpitaux de Paris (AP-HP), Laboratoire d'Hématologie, Hôpital Saint Louis, Paris, France. christine.chomienne@sls.aphp.fr.
authors.forename: Christine
authors.initials: C
authors.lastname: Chomienne
authors.affiliation: Université Paris-Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Unité Mixte de Recherche (UMR-S) 1131, Paris, France. patricia.krief@inserm.fr.|Institut National de la Santé et de la Recherche Médicale (INSERM) Unité (U) 1131, Paris, France. patricia.krief@inserm.fr.
authors.forename: Patricia
authors.initials: P
authors.lastname: Krief
mesh_terms: D000208:Acute Disease; D000818:Animals; D004195:Disease Models, Animal; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D015398:Signal Transduction / Q000235:genetics*
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