与逆转录病毒 CAR 转导 ATM 缺陷 T 细胞有关的遗传毒性。

IF 11.5 Q1 HEMATOLOGY
Meir Rozenbaum, Reut Fluss, Victoria Marcu-Malina, Ifat Sarouk, Amilia Meir, Sarah Elitzur, Tal Zinger, Jasmine Jacob-Hirsch, Efrat G Saar, Gideon Rechavi, Elad Jacoby
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引用次数: 0

摘要

血液恶性肿瘤中普遍存在 DNA 损伤应答基因(如 ATM)的体细胞变异。ATM 蛋白对双链 DNA 断裂修复至关重要。ATM基因缺陷是共济失调性脊髓侧索硬化症(A-T)的病因,这种疾病表现为放射敏感、免疫缺陷和易患淋巴恶性肿瘤。被确诊为恶性肿瘤的共济失调-特朗吉克斯病患者对化疗或放疗的耐受性很差。我们利用A-T患者(ATM-/-)、杂合子供体(ATM+/-)和健康供体的原代T细胞研究了嵌合抗原受体(CAR)T细胞。ATM-/-T细胞能增殖并成功转导CAR,但也观察到ATM-/-CAR-T细胞功能受损。逆转录病毒转导ATM-/-T细胞的CAR导致CAR插入位点的染色体病变率很高,下一代长读测序证实了这一点。这项工作表明,在逆转录病毒制造过程中,ATM 对保持 CAR-T 细胞基因组的完整性至关重要,缺乏它将带来染色体易位和潜在致白血病的风险。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Genotoxicity Associated with Retroviral CAR Transduction of ATM-Deficient T Cells.

Somatic variants in DNA damage response genes such as ATM are widespread in hematologic malignancies. ATM protein is essential for double-strand DNA break repair. Germline ATM deficiencies underlie ataxia-telangiectasia (A-T), a disease manifested by radiosensitivity, immunodeficiency, and predisposition to lymphoid malignancies. Patients with A-T diagnosed with malignancies have poor tolerance to chemotherapy or radiation. In this study, we investigated chimeric antigen receptor (CAR) T cells using primary T cells from patients with A-T (ATM-/-), heterozygote donors (ATM+/-), and healthy donors. ATM-/- T cells proliferate and can be successfully transduced with CARs, though functional impairment of ATM-/- CAR T-cells was observed. Retroviral transduction of the CAR in ATM-/- T cells resulted in high rates of chromosomal lesions at CAR insertion sites, as confirmed by next-generation long-read sequencing. This work suggests that ATM is essential to preserve genome integrity of CAR T-cells during retroviral manufacturing, and its lack poses a risk of chromosomal translocations and potential leukemogenicity. Significance: CAR T-cells are clinically approved genetically modified cells, but the control of genome integrity remains largely uncharacterized. This study demonstrates that ATM deficiency marginally impairs CAR T-cell function and results in high rates of chromosomal aberrations after retroviral transduction, which may be of concern in patients with DNA repair deficiencies.

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来源期刊
CiteScore
12.70
自引率
1.80%
发文量
139
期刊介绍: The journal Blood Cancer Discovery publishes high-quality Research Articles and Briefs that focus on major advances in basic, translational, and clinical research of leukemia, lymphoma, myeloma, and associated diseases. The topics covered include molecular and cellular features of pathogenesis, therapy response and relapse, transcriptional circuits, stem cells, differentiation, microenvironment, metabolism, immunity, mutagenesis, and clonal evolution. These subjects are investigated in both animal disease models and high-dimensional clinical data landscapes. The journal also welcomes submissions on new pharmacological, biological, and living cell therapies, as well as new diagnostic tools. They are interested in prognostic, diagnostic, and pharmacodynamic biomarkers, and computational and machine learning approaches to personalized medicine. The scope of submissions ranges from preclinical proof of concept to clinical trials and real-world evidence. Blood Cancer Discovery serves as a forum for diverse ideas that shape future research directions in hematooncology. In addition to Research Articles and Briefs, the journal also publishes Reviews, Perspectives, and Commentaries on topics of broad interest in the field.
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