Abstract 4059: CRISPR-EXO - genetic deletion tool for treating chronic myelogenous leukemia
| العنوان: | Abstract 4059: CRISPR-EXO - genetic deletion tool for treating chronic myelogenous leukemia |
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| المؤلفون: | Duško Lainšček, Špela Malenšek, Mojca Skrbinek, Matjaž Sever, Vida Forstnerič, Roman Jerala |
| المصدر: | Cancer Research. 80:4059-4059 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Cancer Research, Cas9, Myeloid leukemia, Cancer, Chromosomal translocation, Biology, medicine.disease, Philadelphia chromosome, Fusion gene, Oncology, hemic and lymphatic diseases, medicine, Cancer research, CRISPR, Chronic myelogenous leukemia |
| الوصف: | Chronic myeloid leukemia (CML) is a myeloproliferative neoplastic disease, occurring in 1 to 2 cases per 100.000 adults, which accounts for ~ 15 % of newly diagnosed leukemias in adult patients. The diagnosis is based upon the genetic translocation between the t(9;22)(q34;q11.2), resulting in the formation of Philadelphia fusion chromosome, coding for BCR-ABL1 oncoprotein. The life-long treatment relies on tyrosine kinase inhibitors (TKIs). In nearly in 2 % patients develop point mutations, leading to resistance to TKIs treatment. New solutions for treating cancer with genetic etiology are considered. CRISPR/Cas system, composed of guide RNA, targeting endonuclease Cas9 to specific target genomic region has been used before to mediate breakage of Philadelphia chromosome at the site of oncogenic translocation. We present a strategy to couple Cas9 to the exonuclease to promote large deletions at the cancer-specific target genomic site. Cotransfection with EXOIII exhibited the best increase in deletion formation of all tested exonucleases. To further improve the rate of genetic lesion formation, Cas9 and EXOIII were connected via coiled-coil heterodimer forming peptides, bringing the two enzymes into close proximity (CRISPR-EXO). This resulted in a potent increase of deletion formation compared to the standard CRISPR/Cas, cotransfection and genetic fusion. We performed an animal study for the use of the CRISPR-EXO system as a potential anti-cancer therapeutic tool. In case of the CRISPR-EXO system, we showed a significant increase in cell death due to higher genome editing in the BCR-ABL1 region. These findings were confirmed also in an animal cancer model, where animals with tumors, electroporated with CRISPR-EXO system showed improved survival and drastic reduction in tumor size.CRISPR-EXO upgraded CRISPR system based on tethering Cas9 protein to exonuclease EXOIII by heterodimeric coiled-coil forming peptides, resulted in highly efficient editing of BCR-ABL1 fusion gene, leading to enhanced death of CML cancer cells. Citation Format: Duško Lainšček, Vida Forstnerič, Špela Malenšek, Mojca Skrbinek, Matjaž Sever, Roman Jerala. CRISPR-EXO - genetic deletion tool for treating chronic myelogenous leukemia [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4059. |
| تدمد: | 1538-7445 0008-5472 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::72d1ac9a80a04478fab94676b411a1f3 https://doi.org/10.1158/1538-7445.am2020-4059 |
| رقم الأكسشن: | edsair.doi...........72d1ac9a80a04478fab94676b411a1f3 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15387445 00085472 |
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