Designing specific chromosomal translocations of the MLL/KMT2A gene

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Chromosomal translocations are the major cause of hemato-malignant cancers. Many of them have been shown to be necessary and sufficient for the onset of leukemias or lymphomas. For some of them, experimental data are still controversial, e.g. the chromosomal translocation t(4;11). Experiments using only the MLL-AF4 fusion protein did never result in cancer development, while the combination of MLL-AF4 and AF4-MLL result in leukemia (see Schneidawind et al. 2018). Here we present a novel CRISPR/CAS9-mediated experimental system to induce specific chromosomal translocations in primary cells or cell lines, by using a "chromosomal homology mediated end joining" (HMEJ) approach. In our case, we used genomic fragments of MLL/KMT2A and AF4/AFF1 to induce specifically a t(4;11) translocation which was subsequently positively (Puromycin) and negatively (Ganciclovir) selected. We present our initial data on this novel and universal system that allow to induce specific genome rearrangements known to cause the oncogenic conversion of normal cells into malignant cells. Publication History Article published online: 17 May 2022 © 2022. Thieme. All rights reserved. Georg Thieme Verlag Rüdigerstraße 14, 70469 Stuttgart, Germany

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