PMID- 27856460
OWN - NLM
STAT- MEDLINE
DCOM- 20170814
LR  - 20210202
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Linking)
VI  - 129
IP  - 4
DP  - 2017 Jan 26
TI  - Architectural and functional heterogeneity of hematopoietic stem/progenitor cells 
      in non-del(5q) myelodysplastic syndromes.
PG  - 484-496
LID - 10.1182/blood-2016-03-707745 [doi]
AB  - 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.
CI  - (c) 2017 by The American Society of Hematology.
FAU - Chesnais, Virginie
AU  - Chesnais V
AD  - Institut Cochin, Paris, France.
AD  - Institut National de la Sante et de la Recherche Medicale INSERM U1016, Paris, 
      France.
AD  - Centre National de la Recherche Scientifique, Unite Mixte de Recherche 8104, 
      Paris, France.
AD  - Universite Paris Descartes, Paris, France.
FAU - Arcangeli, Marie-Laure
AU  - Arcangeli ML
AD  - INSERM Unite Mixte de Recherche 967, Commissariat a l'Energie 
      Atomique/Departement des Sciences de la Vie/Institut de Recherche en 
      Radiobiologie Cellulaire et Moleculaire Laboratory of Hematopoietic Stem Cells 
      and Leukemic Cells, Equipe Labellisee par la Ligue Nationale Contre le Cancer, 
      Universite Paris Diderot, Universite Paris-Saclay, Commissariat a l'Energie 
      Atomique et aux Energies Alternatives, Fontenay-aux-Roses, France.
FAU - Delette, Caroline
AU  - Delette C
AD  - Institut Cochin, Paris, France.
AD  - Institut National de la Sante et de la Recherche Medicale INSERM U1016, Paris, 
      France.
AD  - Centre National de la Recherche Scientifique, Unite Mixte de Recherche 8104, 
      Paris, France.
AD  - Universite Paris Descartes, Paris, France.
FAU - Rousseau, Alice
AU  - Rousseau A
AD  - Institut Cochin, Paris, France.
AD  - Institut National de la Sante et de la Recherche Medicale INSERM U1016, Paris, 
      France.
AD  - Centre National de la Recherche Scientifique, Unite Mixte de Recherche 8104, 
      Paris, France.
AD  - Universite Paris Descartes, Paris, France.
AD  - Assistance Publique-Hopitaux de Paris, Service d'Hematologie Biologique, Hopitaux 
      Universitaires Paris Centre, Paris, France.
FAU - Guermouche, Helene
AU  - Guermouche H
AD  - Institut Cochin, Paris, France.
AD  - Institut National de la Sante et de la Recherche Medicale INSERM U1016, Paris, 
      France.
AD  - Centre National de la Recherche Scientifique, Unite Mixte de Recherche 8104, 
      Paris, France.
AD  - Universite Paris Descartes, Paris, France.
AD  - Assistance Publique-Hopitaux de Paris, Service d'Hematologie Biologique, Hopitaux 
      Universitaires Paris Centre, Paris, France.
FAU - Lefevre, Carine
AU  - Lefevre C
AD  - Institut Cochin, Paris, France.
AD  - Institut National de la Sante et de la Recherche Medicale INSERM U1016, Paris, 
      France.
AD  - Centre National de la Recherche Scientifique, Unite Mixte de Recherche 8104, 
      Paris, France.
AD  - Universite Paris Descartes, Paris, France.
FAU - Bondu, Sabrina
AU  - Bondu S
AD  - Institut Cochin, Paris, France.
AD  - Institut National de la Sante et de la Recherche Medicale INSERM U1016, Paris, 
      France.
AD  - Centre National de la Recherche Scientifique, Unite Mixte de Recherche 8104, 
      Paris, France.
AD  - Universite Paris Descartes, Paris, France.
FAU - Diop, M'boyba
AU  - Diop M
AD  - INSERM U1170, Equipe Labellisee Ligue Nationale Contre le Cancer, Universite 
      Paris-Saclay, Institut Gustave Roussy, Villejuif, France.
FAU - Cheok, Meyling
AU  - Cheok M
AD  - INSERM, Centre Hospitalier Universitaire Lille, Unite de Mixte de 
      Recherche-Scientifique 1172, Jean-Pierre Aubert Research Center, Lille, France.
FAU - Chapuis, Nicolas
AU  - Chapuis N
AD  - Institut Cochin, Paris, France.
AD  - Institut National de la Sante et de la Recherche Medicale INSERM U1016, Paris, 
      France.
AD  - Centre National de la Recherche Scientifique, Unite Mixte de Recherche 8104, 
      Paris, France.
AD  - Universite Paris Descartes, Paris, France.
AD  - Assistance Publique-Hopitaux de Paris, Service d'Hematologie Biologique, Hopitaux 
      Universitaires Paris Centre, Paris, France.
FAU - Legros, Laurence
AU  - Legros L
AD  - Service de Medecine Interne, Centre Hospitalier Universitaire, Nice, France.
FAU - Raynaud, Sophie
AU  - Raynaud S
AD  - Laboratoire d'Hematologie Centre Hospitalier Universitaire, Nice, France; and.
FAU - Willems, Lise
AU  - Willems L
AD  - Assistance Publique-Hopitaux de Paris, Service d'Hematologie, Hopitaux 
      Universitaires Paris Centre, Paris, France.
FAU - Bouscary, Didier
AU  - Bouscary D
AD  - Institut Cochin, Paris, France.
AD  - Institut National de la Sante et de la Recherche Medicale INSERM U1016, Paris, 
      France.
AD  - Centre National de la Recherche Scientifique, Unite Mixte de Recherche 8104, 
      Paris, France.
AD  - Universite Paris Descartes, Paris, France.
AD  - Assistance Publique-Hopitaux de Paris, Service d'Hematologie, Hopitaux 
      Universitaires Paris Centre, Paris, France.
FAU - Lauret, Evelyne
AU  - Lauret E
AD  - Institut Cochin, Paris, France.
AD  - Institut National de la Sante et de la Recherche Medicale INSERM U1016, Paris, 
      France.
AD  - Centre National de la Recherche Scientifique, Unite Mixte de Recherche 8104, 
      Paris, France.
AD  - Universite Paris Descartes, Paris, France.
FAU - Bernard, Olivier A
AU  - Bernard OA
AD  - INSERM U1170, Equipe Labellisee Ligue Nationale Contre le Cancer, Universite 
      Paris-Saclay, Institut Gustave Roussy, Villejuif, France.
FAU - Kosmider, Olivier
AU  - Kosmider O
AD  - Institut Cochin, Paris, France.
AD  - Institut National de la Sante et de la Recherche Medicale INSERM U1016, Paris, 
      France.
AD  - Centre National de la Recherche Scientifique, Unite Mixte de Recherche 8104, 
      Paris, France.
AD  - Universite Paris Descartes, Paris, France.
AD  - Assistance Publique-Hopitaux de Paris, Service d'Hematologie Biologique, Hopitaux 
      Universitaires Paris Centre, Paris, France.
FAU - Pflumio, Francoise
AU  - Pflumio F
AD  - INSERM Unite Mixte de Recherche 967, Commissariat a l'Energie 
      Atomique/Departement des Sciences de la Vie/Institut de Recherche en 
      Radiobiologie Cellulaire et Moleculaire Laboratory of Hematopoietic Stem Cells 
      and Leukemic Cells, Equipe Labellisee par la Ligue Nationale Contre le Cancer, 
      Universite Paris Diderot, Universite Paris-Saclay, Commissariat a l'Energie 
      Atomique et aux Energies Alternatives, Fontenay-aux-Roses, France.
FAU - Fontenay, Michaela
AU  - Fontenay M
AD  - Institut Cochin, Paris, France.
AD  - Institut National de la Sante et de la Recherche Medicale INSERM U1016, Paris, 
      France.
AD  - Centre National de la Recherche Scientifique, Unite Mixte de Recherche 8104, 
      Paris, France.
AD  - Universite Paris Descartes, Paris, France.
AD  - Assistance Publique-Hopitaux de Paris, Service d'Hematologie Biologique, Hopitaux 
      Universitaires Paris Centre, Paris, France.
LA  - eng
PT  - Journal Article
DEP - 20161116
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Antigens, CD34)
RN  - 0 (Antigens, Nuclear)
RN  - 0 (BCOR protein, human)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (Membrane Glycoproteins)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Repressor Proteins)
RN  - 0 (STAG2 protein, human)
RN  - EC 3.2.2.5 (CD38 protein, human)
RN  - EC 3.2.2.6 (ADP-ribosyl Cyclase 1)
SB  - IM
MH  - ADP-ribosyl Cyclase 1/deficiency/genetics
MH  - Animals
MH  - Antigens, CD34/genetics/metabolism
MH  - Antigens, Nuclear/genetics/metabolism
MH  - Cell Cycle Proteins
MH  - Cell Differentiation
MH  - Cell Lineage/genetics
MH  - *Chromosomes, Human, Pair 5
MH  - Clone Cells
MH  - Disease Progression
MH  - Female
MH  - Gene Expression
MH  - Gene Knockdown Techniques
MH  - Hematopoietic Stem Cells/*metabolism/pathology
MH  - Humans
MH  - Immunophenotyping
MH  - Leukemia, Myeloid, Acute/complications/*genetics/metabolism/pathology
MH  - Lymphocytes/*metabolism/pathology
MH  - Membrane Glycoproteins/deficiency/genetics
MH  - Mice
MH  - Mice, Inbred NOD
MH  - *Mutation
MH  - Myelodysplastic Syndromes/complications/*genetics/metabolism/pathology
MH  - Myeloid Cells/*metabolism/pathology
MH  - Phenotype
MH  - Proto-Oncogene Proteins/genetics/metabolism
MH  - Repressor Proteins/genetics/metabolism
MH  - Transplantation, Heterologous
EDAT- 2016/11/20 06:00
MHDA- 2017/08/15 06:00
CRDT- 2016/11/19 06:00
PHST- 2016/03/26 00:00 [received]
PHST- 2016/11/06 00:00 [accepted]
PHST- 2016/11/20 06:00 [pubmed]
PHST- 2017/08/15 06:00 [medline]
PHST- 2016/11/19 06:00 [entrez]
AID - S0006-4971(20)33757-5 [pii]
AID - 10.1182/blood-2016-03-707745 [doi]
PST - ppublish
SO  - Blood. 2017 Jan 26;129(4):484-496. doi: 10.1182/blood-2016-03-707745. Epub 2016 
      Nov 16.