The role of reciprocal fusions in MLL-r acute leukemia: studying the chromosomal translocation t(4;11)
Open Access
- 6 September 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 40 (42), 6093-6102
- https://doi.org/10.1038/s41388-021-02001-2
Abstract
Leukemia patients bearing the t(4;11)(q21;q23) translocations can be divided into two subgroups: those expressing both reciprocal fusion genes, and those that have only the MLL-AF4 fusion gene. Moreover, a recent study has demonstrated that patients expressing both fusion genes have a better outcome than patients that are expressing the MLL-AF4 fusion protein alone. All this may point to a clonal process where the reciprocal fusion gene AF4-MLL could be lost during disease progression, as this loss may select for a more aggressive type of leukemia. Therefore, we were interested in unraveling the decisive role of the AF4-MLL fusion protein at an early timepoint of disease development. We designed an experimental model system where the MLL-AF4 fusion protein was constitutively expressed, while an inducible AF4-MLL fusion gene was induced for only 48 h. Subsequently, we investigated genome-wide changes by RNA- and ATAC-Seq experiments at distinct timepoints. These analyses revealed that the expression of AF4-MLL for only 48 h was sufficient to significantly change the genomic landscape (transcription and chromatin) even on a longer time scale. Thus, we have to conclude that the AF4-MLL fusion protein works through a hit-and-run mechanism, probably necessary to set up pre-leukemic conditions, but being dispensable for later disease progression.Funding Information
- Deutsche Forschungsgemeinschaft (Ma 1876/12-1, Ma 1876/13-1)
- Wilhelm Sander-Stiftung (2018.070.1, 2018.070.2)
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