Clonal tracking in gene therapy patients reveals a diversity of human hematopoietic differentiation programs.
Journal
Blood
ISSN: 1528-0020
Titre abrégé: Blood
Pays: United States
ID NLM: 7603509
Informations de publication
Date de publication:
09 04 2020
09 04 2020
Historique:
received:
11
07
2019
accepted:
21
01
2020
pubmed:
11
2
2020
medline:
3
11
2020
entrez:
11
2
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32040546
pii: S0006-4971(20)62115-2
doi: 10.1182/blood.2019002350
pmc: PMC7146019
doi:
Types de publication
Clinical Trial
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1219-1231Subventions
Organisme : NIAID NIH HHS
ID : R01 AI082020
Pays : United States
Organisme : NIAID NIH HHS
ID : U19 AI117950
Pays : United States
Organisme : NIAID NIH HHS
ID : P30 AI045008
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI052845
Pays : United States
Organisme : Wellcome Trust
ID : 090233/Z/09/Z
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2020 by The American Society of Hematology.
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