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Blood. 2017 Jan 26;129(4):484-496. doi: 10.1182/blood-2016-03-707745. Epub 2016 Nov 16.

Architectural and functional heterogeneity of hematopoietic stem/progenitor cells in non-del(5q) myelodysplastic syndromes.

Chesnais V1,2,3,4, Arcangeli ML5, Delette C1,2,3,4, Rousseau A1,2,3,4,6, Guermouche H1,2,3,4,6, Lefevre C1,2,3,4, Bondu S1,2,3,4, Diop M7, Cheok M8, Chapuis N1,2,3,4,6, Legros L9, Raynaud S10, Willems L11, Bouscary D1,2,3,4,11, Lauret E1,2,3,4, Bernard OA7, Kosmider O1,2,3,4,6, Pflumio F5, Fontenay M1,2,3,4,6.

Author information

1
Institut Cochin, Paris, France.
2
Institut National de la Santé et de la Recherche Médicale INSERM U1016, Paris, France.
3
Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, Paris, France.
4
Université Paris Descartes, Paris, France.
5
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.
6
Assistance Publique-Hôpitaux de Paris, Service d'Hématologie Biologique, Hôpitaux Universitaires Paris Centre, Paris, France.
7
INSERM U1170, Equipe Labellisée Ligue Nationale Contre le Cancer, Université Paris-Saclay, Institut Gustave Roussy, Villejuif, France.
8
INSERM, Centre Hospitalier Universitaire Lille, Unité de Mixte de Recherche-Scientifique 1172, Jean-Pierre Aubert Research Center, Lille, France.
9
Service de Médecine Interne, Centre Hospitalier Universitaire, Nice, France.
10
Laboratoire d'Hématologie Centre Hospitalier Universitaire, Nice, France; and.
11
Assistance Publique-Hôpitaux de Paris, Service d'Hématologie, Hôpitaux Universitaires Paris Centre, Paris, France.

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.

PMID:
27856460
DOI:
10.1182/blood-2016-03-707745
[Indexed for MEDLINE]
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