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Mol Ther. 2019 Jun 5;27(6):1074-1086. doi: 10.1016/j.ymthe.2019.04.003. Epub 2019 Apr 9.

Aberrant Clonal Hematopoiesis following Lentiviral Vector Transduction of HSPCs in a Rhesus Macaque.

Author information

1
Translational Stem Cell Biology Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892, USA; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
2
Translational Stem Cell Biology Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892, USA.
3
Translational Stem Cell Biology Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892, USA; Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
4
Sickle Cell and Vascular Biology Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD, USA.
5
Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, Canada.
6
Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of Southern California, Los Angeles, CA, USA.
7
Cancer Research Technology Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
8
Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA.
9
Translational Stem Cell Biology Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892, USA. Electronic address: wuc3@mail.nih.gov.
10
Translational Stem Cell Biology Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892, USA. Electronic address: dunbarc@nhlbi.nih.gov.

Abstract

Lentiviral vectors (LVs) are used for delivery of genes into hematopoietic stem and progenitor cells (HSPCs) in clinical trials worldwide. LVs, in contrast to retroviral vectors, are not associated with insertion site-associated malignant clonal expansions and, thus, are considered safer. Here, however, we present a case of markedly abnormal dysplastic clonal hematopoiesis affecting the erythroid, myeloid, and megakaryocytic lineages in a rhesus macaque transplanted with HSPCs that were transduced with a LV containing a strong retroviral murine stem cell virus (MSCV) constitutive promoter-enhancer in the LTR. Nine insertions were mapped in the abnormal clone, resulting in overexpression and aberrant splicing of several genes of interest, including the cytokine stem cell factor and the transcription factor PLAG1. This case represents the first clear link between lentiviral insertion-induced clonal expansion and a clinically abnormal transformed phenotype following transduction of normal primate or human HSPCs, which is concerning, and suggests that strong constitutive promoters should not be included in LVs.

KEYWORDS:

gene therapy; genotoxicity; lentiviral vector; non-human primate

PMID:
31023523
PMCID:
PMC6554657
[Available on 2020-06-05]
DOI:
10.1016/j.ymthe.2019.04.003

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