Journal
MOLECULAR THERAPY
Volume 27, Issue 6, Pages 1074-1086Publisher
CELL PRESS
DOI: 10.1016/j.ymthe.2019.04.003
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Funding
- NHLBI Division of Intramural Research
- Scientific Research Training Program for Young Talents - Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [ZIAHL006008, ZIAHL002339, ZIAHL002338] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [ZIAAI000644, ZIAAI000645] Funding Source: NIH RePORTER
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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 promoterenhancer 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.
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