| Autor: |
Neldeborg, Signe, Soerensen, Johannes Frasez, Møller, Charlotte Thornild, Bill, Marie, Gao, Zongliang, Bak, Rasmus O., Holm, Kasper, Sorensen, Boe, Nyegaard, Mette, Luo, Yonglun, Hokland, Peter, Stougaard, Magnus, Ludvigsen, Maja, Holm, Christian Kanstrup |
| Zdroj: |
Leukemia; 20230101, Issue: Preprints p1-10, 10p |
| Abstrakt: |
Oncogenic fusion drivers are common in hematological cancers and are thus relevant targets of future CRISPR-Cas9-based treatment strategies. However, breakpoint-location variation in patients pose a challenge to traditional breakpoint-targeting CRISPR-Cas9-mediated disruption strategies. Here we present a new dual intron-targeting CRISPR-Cas9 treatment strategy, for targeting t(8;21) found in 5–10% of de novo acute myeloid leukemia (AML), which efficiently disrupts fusion genes without prior identification of breakpoint location. We show in vitro growth rate and proliferation reduction by 69 and 94% in AML t(8;21) Kasumi-1 cells, following dual intron-targeted disruption of RUNX1-RUNX1T1compared to a non t(8;21) AML control. Furthermore, mice injected with RUNX1-RUNX1T1-disrupted Kasumi-1 cells had in vivo tumor growth reduction by 69 and 91% compared to controls. Demonstrating the feasibility of RUNX1-RUNX1T1disruption, these findings were substantiated in isolated primary cells from a patient diagnosed with AML t(8;21). In conclusion, we demonstrate proof-of-principle of a dual intron-targeting CRISPR-Cas9 treatment strategy in AML t(8;21) without need for precise knowledge of the breakpoint location. |
| Databáze: |
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