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• W2564697737 abstract "The historical model of hematopoiesis, mainly derived from murine studies, is based on the existence of a single hematopoietic stem cell (HSC) capable of generating all blood cell lineages. However this model has been challenged by the proposal of four types of murine HSC, which differ by their contribution to the myeloid and lymphoid lineages. Here we have used data from a gene therapy trial to treat Wiskott-Aldrich syndrome (WAS) to explore hematopoiesis in humans. In the trial, the therapeutic vector (lentivirus) integrates into the genome at unique positions in each hematopoietic stem and progenitor cell and is consequently transmitted to all its progeny. Thus hematopoietic ontogeny in humans can be inferred by tracking the appearance of unique integration sites in fractionated blood cell populations. This provides a unique opportunity to model the developmental complexity of the human haematological system. Considerable effort over the last 15 years has been devoted to optimizing retroviral integration sites (RIS) analysis using ligation mediated PCR (LM-PCR), combined with acoustic shearing and high-throughput Illumina sequencing. Acoustic shearing enables more precise quantification of RIS abundance through the enumeration of the various sizes of shear fragments containing a given RIS, which correspond to individual cells in the starting blood cell populations. In addition, the great diversity of these clonal populations results in very sparse samples for many clones, necessitating the development of statistical methods to account for unsampled cell fractions. In four WAS patients treated by gene therapy, we have sorted peripheral blood samples for 5 cell types: myeloid (granulocytes and monocytes) and lymphoid subpopulations (T, B and NK cells), and analysed their RIS profile. Each RIS corresponds to a particular stem/progenitor cell clone, with a particular pattern defined by its presence or absence in each of the 5 lineages. These data are then use to reconstruct aspects of the hematopoietic hierarchy. In order to face the challenging issue of cell sorting contamination we have been using a stringent sort precision mode and we treat residual contamination explicitly in downstream statistical models. Using these approaches, we have characterized up to tens of thousands RIS per patient with a follow up of 4 years. We showed that a large fraction of RIS clones are detected in a single lineage, while other RIS clones are characterized by different levels of contribution to the myeloid and lymphoid lineages, highlighting the heterogeneity of human HSCs. Clones contributing to all 5 lineages are readily recovered but do not constitute the majority of the population. Longitudinal analysis of clonal dynamics is ongoing. These new findings provide unique data on human hematopoiesis in gene corrected WAS patients." @default.
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• W2564697737 date "2016-05-01" @default.
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• W2564697737 title "754. Exploring the Human Hematopoietic Hierarchy Through Retroviral Integration Sites Tracking in the Wiskott Aldrich Syndrome Gene Therapy Trial" @default.
• W2564697737 doi "https://doi.org/10.1016/s1525-0016(16)33562-6" @default.
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