ABL Genomic Editing Sufficiently Abolishes Oncogenesis of Human Chronic Myeloid Leukemia Cells In Vitro and In Vivo
| Autor: | Chun-Yu Lin, Kai Wen Hsu, Ming Jang Su, Chia Hwa Lee, Su Mei Lin, Yun Shan Chiang, Wen Shyang Hsieh, Shu Huey Chen, Huey En Tzeng, Yao Yu Hsieh |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
gene edit Cancer Research Biology Philadelphia chromosome medicine.disease_cause lcsh:RC254-282 Article 03 medical and health sciences 0302 clinical medicine hemic and lymphatic diseases medicine neoplasms CRISPR/Cas9 BCR-ABL CML ABL Myeloid leukemia Imatinib medicine.disease lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Leukemia 030104 developmental biology Oncology 030220 oncology & carcinogenesis Cancer research Carcinogenesis medicine.drug Chronic myelogenous leukemia K562 cells |
| Zdroj: | Cancers, Vol 12, Iss 1399, p 1399 (2020) Cancers Volume 12 Issue 6 |
| ISSN: | 2072-6694 |
| Popis: | Chronic myelogenous leukemia (CML) is the most common type of leukemia in adults, and more than 90% of CML patients harbor the abnormal Philadelphia chromosome (Ph) that encodes the BCR-ABL oncoprotein. Although the ABL kinase inhibitor (imatinib) has proven to be very effective in achieving high remission rates and improving prognosis, up to 33% of CML patients still cannot achieve an optimal response. Here, we used CRISPR/Cas9 to specifically target the BCR-ABL junction region in K562 cells, resulting in the inhibition of cancer cell growth and oncogenesis. Due to the variety of BCR-ABL junctions in CML patients, we utilized gene editing of the human ABL gene for clinical applications. Using the ABL gene-edited virus in K562 cells, we detected 41.2% indels in ABL sgRNA_2-infected cells. The ABL-edited cells reveled significant suppression of BCR-ABL protein expression and downstream signals, inhibiting cell growth and increasing cell apoptosis. Next, we introduced the ABL gene-edited virus into a systemic K562 leukemia xenograft mouse model, and bioluminescence imaging of the mice showed a significant reduction in the leukemia cell population in ABL-targeted mice, compared to the scramble sgRNA virus-injected mice. In CML cells from clinical samples, infection with the ABL gene-edited virus resulted in more than 30.9% indels and significant cancer cell death. Notably, no off-target effects or bone marrow cell suppression was found using the ABL gene-edited virus, ensuring both user safety and treatment efficacy. This study demonstrated the critical role of the ABL gene in maintaining CML cell survival and tumorigenicity in vitro and in vivo. ABL gene editing-based therapy might provide a potential strategy for imatinib-insensitive or resistant CML patients. |
| Databáze: | OpenAIRE |
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