標題: | ABLGenomic Editing Sufficiently Abolishes Oncogenesis of Human Chronic Myeloid Leukemia Cells In Vitro and In Vivo |
作者: | Chen, Shu-Huey Hsieh, Yao-Yu Tzeng, Huey-En Lin, Chun-Yu Hsu, Kai-Wen Chiang, Yun-Shan Lin, Su-Mei Su, Ming-Jang Hsieh, Wen-Shyang Lee, Chia-Hwa 交大名義發表 生物資訊及系統生物研究所 National Chiao Tung University Institude of Bioinformatics and Systems Biology |
關鍵字: | CRISPR;Cas9;gene edit;Philadelphia chromosome;BCR-ABL;CML |
公開日期: | 1-Jun-2020 |
摘要: | 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 theBCR-ABLjunction region in K562 cells, resulting in the inhibition of cancer cell growth and oncogenesis. Due to the variety ofBCR-ABLjunctions in CML patients, we utilized gene editing of the humanABLgene for clinical applications. Using theABLgene-edited virus in K562 cells, we detected 41.2% indels inABLsgRNA_2-infected cells. TheABL-edited cells reveled significant suppression of BCR-ABL protein expression and downstream signals, inhibiting cell growth and increasing cell apoptosis. Next, we introduced theABLgene-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 inABL-targeted mice, compared to the scramble sgRNA virus-injected mice. In CML cells from clinical samples, infection with theABLgene-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 theABLgene-edited virus, ensuring both user safety and treatment efficacy. This study demonstrated the critical role of theABLgene in maintaining CML cell survival and tumorigenicity in vitro and in vivo.ABLgene editing-based therapy might provide a potential strategy for imatinib-insensitive or resistant CML patients. |
URI: | http://dx.doi.org/10.3390/cancers12061399 http://hdl.handle.net/11536/154900 |
DOI: | 10.3390/cancers12061399 |
期刊: | CANCERS |
Volume: | 12 |
Issue: | 6 |
起始頁: | 0 |
結束頁: | 0 |
Appears in Collections: | Articles |