Clonal tracking in gene therapy patients reveals a diversity of human hematopoietic differentiation programs.

Autor:	Six E; INSERM UMR 1163, Laboratory of Human Lymphohematopoiesis, Paris, France.; Imagine Institute, Paris Descartes-Sorbonne Paris Cité University, Paris, France., Guilloux A; Laboratoire de Mathématiques et Modélisation d'Evry, CNRS, Paris-Saclay University, Evry University, Evry, France., Denis A; INSERM UMR 1163, Laboratory of Human Lymphohematopoiesis, Paris, France.; Imagine Institute, Paris Descartes-Sorbonne Paris Cité University, Paris, France., Lecoules A; INSERM UMR 1163, Laboratory of Human Lymphohematopoiesis, Paris, France.; Imagine Institute, Paris Descartes-Sorbonne Paris Cité University, Paris, France., Magnani A; Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpitaux de Paris, INSERM, Paris, France., Vilette R; Laboratoire de Mathématiques et Modélisation d'Evry, CNRS, Paris-Saclay University, Evry University, Evry, France., Male F; Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, PA., Cagnard N; Imagine Institute, Paris Descartes-Sorbonne Paris Cité University, Paris, France.; Structure Fédérative de Recherche Necker, Bioinformatic Platform, Paris, France., Delville M; INSERM UMR 1163, Laboratory of Human Lymphohematopoiesis, Paris, France.; Imagine Institute, Paris Descartes-Sorbonne Paris Cité University, Paris, France., Magrin E; Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpitaux de Paris, INSERM, Paris, France., Caccavelli L; Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpitaux de Paris, INSERM, Paris, France., Roudaut C; Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpitaux de Paris, INSERM, Paris, France., Plantier C; Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpitaux de Paris, INSERM, Paris, France., Sobrino S; INSERM UMR 1163, Laboratory of Human Lymphohematopoiesis, Paris, France.; Imagine Institute, Paris Descartes-Sorbonne Paris Cité University, Paris, France., Gregg J; Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, PA., Nobles CL; Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, PA., Everett JK; Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, PA., Hacein-Bey-Abina S; Clinical Immunology Laboratory, Groupe Hospitalier Universitaire Paris-Sud, Kremlin-Bicêtre Hospital, Assistance Publique-Hôpitaux de Paris, Le Kremlin Bicetre, France.; Unité de Technologies Chimiques et Biologiques pour la Santé (UTCBS), CNRS UMR 8258, INSERM U1267, Faculté de Pharmacie de Paris, Université Paris Descartes, Chimie ParisTech, Paris, France., Galy A; Genethon, Evry, France.; Inserm UMR S951, Evry University, Paris-Saclay University, Evry, France., Fischer A; Imagine Institute, Paris Descartes-Sorbonne Paris Cité University, Paris, France.; Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.; INSERM UMR 1163, Paris, France.; College de France, Paris, France; and., Thrasher AJ; Great Ormond Street, Institute of Child Health, Molecular and Cellular Immunology, University College London, United Kingdom., André I; INSERM UMR 1163, Laboratory of Human Lymphohematopoiesis, Paris, France.; Imagine Institute, Paris Descartes-Sorbonne Paris Cité University, Paris, France., Cavazzana M; INSERM UMR 1163, Laboratory of Human Lymphohematopoiesis, Paris, France.; Imagine Institute, Paris Descartes-Sorbonne Paris Cité University, Paris, France.; Structure Fédérative de Recherche Necker, Bioinformatic Platform, Paris, France., Bushman FD; Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, PA.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2020 Apr 09; Vol. 135 (15), pp. 1219-1231.
DOI:	10.1182/blood.2019002350
Abstrakt:	In gene therapy with human hematopoietic stem and progenitor cells (HSPCs), each gene-corrected cell and its progeny are marked in a unique way by the integrating vector. This feature enables lineages to be tracked by sampling blood cells and using DNA sequencing to identify the vector integration sites. Here, we studied 5 cell lineages (granulocytes, monocytes, T cells, B cells, and natural killer cells) in patients having undergone HSPC gene therapy for Wiskott-Aldrich syndrome or β hemoglobinopathies. We found that the estimated minimum number of active, repopulating HSPCs (which ranged from 2000 to 50 000) was correlated with the number of HSPCs per kilogram infused. We sought to quantify the lineage output and dynamics of gene-modified clones; this is usually challenging because of sparse sampling of the various cell types during the analytical procedure, contamination during cell isolation, and different levels of vector marking in the various lineages. We therefore measured the residual contamination and corrected our statistical models accordingly to provide a rigorous analysis of the HSPC lineage output. A cluster analysis of the HSPC lineage output highlighted the existence of several stable, distinct differentiation programs, including myeloid-dominant, lymphoid-dominant, and balanced cell subsets. Our study evidenced the heterogeneous nature of the cell lineage output from HSPCs and provided methods for analyzing these complex data. (© 2020 by The American Society of Hematology.)
Databáze:	MEDLINE
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