دورية أكاديمية
3’ UTR-truncated HMGA2 overexpression induces non-malignant in vivo expansion of hematopoietic stem cells in non-human primates
| العنوان: | 3’ UTR-truncated HMGA2 overexpression induces non-malignant in vivo expansion of hematopoietic stem cells in non-human primates |
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| المؤلفون: | Melissa A. Bonner, Antonio Morales-Hernández, Sheng Zhou, Zhijun Ma, Jose Condori, Yong-Dong Wang, Soghra Fatima, Lance E. Palmer, Laura J. Janke, Stephanie Fowler, Brian P. Sorrentino, Shannon McKinney-Freeman |
| المصدر: | Molecular Therapy: Methods & Clinical Development, Vol 21, Iss , Pp 693-701 (2021) |
| بيانات النشر: | Elsevier |
| سنة النشر: | 2021 |
| المجموعة: | Directory of Open Access Journals: DOAJ Articles |
| مصطلحات موضوعية: | gene therapy, HMGA2, clonal expansion, hematopoietic stem cells, Genetics, QH426-470, Cytology, QH573-671 |
| الوصف: | Vector-mediated mutagenesis remains a major safety concern for many gene therapy clinical protocols. Indeed, lentiviral-based gene therapy treatments of hematologic disease can result in oligoclonal blood reconstitution in the transduced cell graft. Specifically, clonal expansion of hematopoietic stem cells (HSCs) highly expressing HMGA2, a chromatin architectural factor found in many human cancers, is reported in patients undergoing gene therapy for hematologic diseases, raising concerns about the safety of these integrations. Here, we show for the first time in vivo multilineage and multiclonal expansion of non-human primate HSCs expressing a 3’ UTR-truncated version of HMGA2 without evidence of any hematologic malignancy >7 years post-transplantation, which is significantly longer than most non-human gene therapy pre-clinical studies. This expansion is accompanied by an increase in HSC survival, cell cycle activation of downstream progenitors, and changes in gene expression led by the upregulation of IGF2BP2, a mRNA binding regulator of survival and proliferation. Thus, we conclude that prolonged ectopic expression of HMGA2 in hematopoietic progenitors is not sufficient to drive hematologic malignancy and is not an acute safety concern in lentiviral-based gene therapy clinical protocols. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 2329-0501 |
| العلاقة: | http://www.sciencedirect.com/science/article/pii/S2329050121000796Test; https://doaj.org/toc/2329-0501Test; https://doaj.org/article/5f0b62c56c53471e968f158d8327efe5Test |
| DOI: | 10.1016/j.omtm.2021.04.013 |
| الإتاحة: | https://doi.org/10.1016/j.omtm.2021.04.013Test https://doaj.org/article/5f0b62c56c53471e968f158d8327efe5Test |
| رقم الانضمام: | edsbas.672E0F24 |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 23290501 |
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| DOI: | 10.1016/j.omtm.2021.04.013 |