Genomic Editing Sufficiently Abolishes Oncogenesis of Human Chronic Myeloid Leukemia Cells In Vitro and In Vivo.

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 - junction region in K562 cells, resulting in the inhibition of cancer cell growth and oncogenesis. Due to the variety of - junctions in CML patients, we utilized gene editing of the human gene for clinical applications. Using the gene-edited virus in K562 cells, we detected 41.2% indels in sgRNA_2-infected cells. The edited cells reveled significant suppression of BCR-ABL protein expression and downstream signals, inhibiting cell growth and increasing cell apoptosis. Next, we introduced the 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 -targeted mice, compared to the scramble sgRNA virus-injected mice. In CML cells from clinical samples, infection with the 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 gene-edited virus, user safety . This study demonstrated the critical role of the gene in maintaining CML cell survival and tumorigenicity in vitro and in vivo. gene editing-based therapy might provide a potential strategy for imatinib-insensitive or resistant CML patients.