title: Architectural and functional heterogeneity of hematopoietic stem/progenitor cells in non-del(5q) myelodysplastic syndromes.
abstract: Myelodysplastic syndromes (MDSs) are hematopoietic stem cell disorders in which recurrent mutations define clonal hematopoiesis. The origin of the phenotypic diversity of non-del(5q) MDS remains unclear. Here, we investigated the clonal architecture of the CD34+CD38-hematopoietic stem/progenitor cell (HSPC) compartment and interrogated dominant clones for MDS-initiating cells. We found that clones mainly accumulate mutations in a linear succession with retention of a dominant subclone. The clone detected in the long-term culture-initiating cell compartment that reconstitutes short-term human hematopoiesis in xenotransplantation models is usually the dominant clone, which gives rise to the myeloid and to a lesser extent to the lymphoid lineage. The pattern of mutations may differ between common myeloid progenitors (CMPs), granulomonocytic progenitors (GMPs), and megakaryocytic-erythroid progenitors (MEPs). Rare STAG2 mutations can amplify at the level of GMPs, from which it may drive the transformation to acute myeloid leukemia. We report that major truncating BCOR gene mutation affecting HSPC and CMP was beneath the threshold of detection in GMP or MEP. Consistently, BCOR knock-down (KD) in normal CD34+progenitors modifies their granulocytic and erythroid differentiation. Clonal architecture of the HSPC compartment and mutations selected during differentiation contribute to the phenotypic heterogeneity of MDS. Defining the hierarchy of driver mutations provides insights into the process of transformation and may guide the search for novel therapeutic strategies.
authors.affiliation: Institut Cochin, Paris, France.|Institut National de la Santé et de la Recherche Médicale INSERM U1016, Paris, France.|Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, Paris, France.|Université Paris Descartes, Paris, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Chesnais
authors.affiliation: INSERM Unité Mixte de Recherche 967, Commissariat à l'Energie Atomique/Département des Sciences de la Vie/Institut de Recherche en Radiobiologie Cellulaire et Moléculaire Laboratory of Hematopoietic Stem Cells and Leukemic Cells, Equipe Labellisée par la Ligue Nationale Contre le Cancer, Université Paris Diderot, Université Paris-Saclay, Commissariat à l'Energie Atomique et aux Energies Alternatives, Fontenay-aux-Roses, France.
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Arcangeli
authors.affiliation: Institut Cochin, Paris, France.|Institut National de la Santé et de la Recherche Médicale INSERM U1016, Paris, France.|Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, Paris, France.|Université Paris Descartes, Paris, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Delette
authors.affiliation: Institut Cochin, Paris, France.|Institut National de la Santé et de la Recherche Médicale INSERM U1016, Paris, France.|Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, Paris, France.|Université Paris Descartes, Paris, France.|Assistance Publique-Hôpitaux de Paris, Service d'Hématologie Biologique, Hôpitaux Universitaires Paris Centre, Paris, France.
authors.forename: Alice
authors.initials: A
authors.lastname: Rousseau
authors.affiliation: Institut Cochin, Paris, France.|Institut National de la Santé et de la Recherche Médicale INSERM U1016, Paris, France.|Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, Paris, France.|Université Paris Descartes, Paris, France.|Assistance Publique-Hôpitaux de Paris, Service d'Hématologie Biologique, Hôpitaux Universitaires Paris Centre, Paris, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Guermouche
authors.affiliation: Institut Cochin, Paris, France.|Institut National de la Santé et de la Recherche Médicale INSERM U1016, Paris, France.|Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, Paris, France.|Université Paris Descartes, Paris, France.
authors.forename: Carine
authors.initials: C
authors.lastname: Lefevre
authors.affiliation: Institut Cochin, Paris, France.|Institut National de la Santé et de la Recherche Médicale INSERM U1016, Paris, France.|Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, Paris, France.|Université Paris Descartes, Paris, France.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Bondu
authors.affiliation: INSERM U1170, Equipe Labellisée Ligue Nationale Contre le Cancer, Université Paris-Saclay, Institut Gustave Roussy, Villejuif, France.
authors.forename: M'boyba
authors.initials: M
authors.lastname: Diop
authors.affiliation: INSERM, Centre Hospitalier Universitaire Lille, Unité de Mixte de Recherche-Scientifique 1172, Jean-Pierre Aubert Research Center, Lille, France.
authors.forename: Meyling
authors.initials: M
authors.lastname: Cheok
authors.affiliation: Institut Cochin, Paris, France.|Institut National de la Santé et de la Recherche Médicale INSERM U1016, Paris, France.|Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, Paris, France.|Université Paris Descartes, Paris, France.|Assistance Publique-Hôpitaux de Paris, Service d'Hématologie Biologique, Hôpitaux Universitaires Paris Centre, Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chapuis
authors.affiliation: Service de Médecine Interne, Centre Hospitalier Universitaire, Nice, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Legros
authors.affiliation: Laboratoire d'Hématologie Centre Hospitalier Universitaire, Nice, France; and.
authors.forename: Sophie
authors.initials: S
authors.lastname: Raynaud
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Service d'Hématologie, Hôpitaux Universitaires Paris Centre, Paris, France.
authors.forename: Lise
authors.initials: L
authors.lastname: Willems
authors.affiliation: Institut Cochin, Paris, France.|Institut National de la Santé et de la Recherche Médicale INSERM U1016, Paris, France.|Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, Paris, France.|Université Paris Descartes, Paris, France.|Assistance Publique-Hôpitaux de Paris, Service d'Hématologie, Hôpitaux Universitaires Paris Centre, Paris, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Bouscary
authors.affiliation: Institut Cochin, Paris, France.|Institut National de la Santé et de la Recherche Médicale INSERM U1016, Paris, France.|Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, Paris, France.|Université Paris Descartes, Paris, France.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Lauret
authors.affiliation: INSERM U1170, Equipe Labellisée Ligue Nationale Contre le Cancer, Université Paris-Saclay, Institut Gustave Roussy, Villejuif, France.
authors.forename: Olivier A
authors.initials: OA
authors.lastname: Bernard
authors.affiliation: Institut Cochin, Paris, France.|Institut National de la Santé et de la Recherche Médicale INSERM U1016, Paris, France.|Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, Paris, France.|Université Paris Descartes, Paris, France.|Assistance Publique-Hôpitaux de Paris, Service d'Hématologie Biologique, Hôpitaux Universitaires Paris Centre, Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Kosmider
authors.affiliation: INSERM Unité Mixte de Recherche 967, Commissariat à l'Energie Atomique/Département des Sciences de la Vie/Institut de Recherche en Radiobiologie Cellulaire et Moléculaire Laboratory of Hematopoietic Stem Cells and Leukemic Cells, Equipe Labellisée par la Ligue Nationale Contre le Cancer, Université Paris Diderot, Université Paris-Saclay, Commissariat à l'Energie Atomique et aux Energies Alternatives, Fontenay-aux-Roses, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Pflumio
authors.affiliation: Institut Cochin, Paris, France.|Institut National de la Santé et de la Recherche Médicale INSERM U1016, Paris, France.|Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, Paris, France.|Université Paris Descartes, Paris, France.|Assistance Publique-Hôpitaux de Paris, Service d'Hématologie Biologique, Hôpitaux Universitaires Paris Centre, Paris, France.
authors.forename: Michaela
authors.initials: M
authors.lastname: Fontenay
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000172:deficiency / Q000235:genetics; D000818:Animals; D018952:Antigens, CD34 / Q000235:genetics / Q000378:metabolism; D034961:Antigens, Nuclear / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D019070:Cell Lineage / Q000235:genetics; D002895:Chromosomes, Human, Pair 5; D002999:Clone Cells; D018450:Disease Progression; D005260:Female; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D016130:Immunophenotyping; D015470:Leukemia, Myeloid, Acute / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008214:Lymphocytes / Q000378:metabolism* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D022423:Myeloid Cells / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous; D000097722:Cohesins
chemical_list: D051997:ADP-ribosyl Cyclase 1; D018952:Antigens, CD34; D034961:Antigens, Nuclear; D018797:Cell Cycle Proteins; D008562:Membrane Glycoproteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; C411984:BCOR protein, human; C508565:STAG2 protein, human; D000097722:Cohesins; C498154:CD38 protein, human