Aberrant Clonal Hematopoiesis following Lentiviral Vector Transduction of HSPCs in a Rhesus Macaque
| Autor: | Katherine R. Calvo, Idalia M. Yabe, Kristin J Hope, Chuanfeng Wu, Xing Fan, Xiaolin Wu, Rong Lu, Aylin C. Bonifacino, Lauren L. Truitt, Stefan Cordes, Di Yang, Robert E. Donahue, Diego A. Espinoza, Cynthia E. Dunbar, So Gun Hong, Suk See DeRavin, Allen E. Krouse, Mark E. Metzger, John F. Tisdale, Harry L. Malech, Selami Demirci, Naoya Uchida |
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| Rok vydání: | 2019 |
| Předmět: |
Myeloid
Genetic enhancement Genetic Vectors Green Fluorescent Proteins Clone (cell biology) Antigens CD34 Stem cell factor Biology Transplantation Autologous Viral vector 03 medical and health sciences Transduction (genetics) 0302 clinical medicine Transduction Genetic Drug Discovery Genetics medicine Animals Protein Splicing Progenitor cell Promoter Regions Genetic Molecular Biology 030304 developmental biology Pharmacology 0303 health sciences Luminescent Agents Lentivirus Hematopoietic Stem Cell Transplantation Terminal Repeat Sequences Genetic Therapy Hematopoietic Stem Cells Macaca mulatta Clone Cells Hematopoiesis Cell biology Mutagenesis Insertional Haematopoiesis medicine.anatomical_structure 030220 oncology & carcinogenesis Commentary Molecular Medicine |
| Zdroj: | Mol Ther |
| ISSN: | 1525-0016 |
| DOI: | 10.1016/j.ymthe.2019.04.003 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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