The role of reciprocal fusions in MLL-r acute leukemia: studying the chromosomal translocation t(4;11)
- 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.
Author: | Alexander WilhelmORCiDGND, Rolf MarschalekORCiDGND |
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URN: | urn:nbn:de:hebis:30:3-634769 |
DOI: | https://doi.org/10.1038/s41388-021-02001-2 |
ISSN: | 1476-5594 |
Parent Title (English): | Oncogene |
Publisher: | Springer Nature |
Place of publication: | London |
Document Type: | Article |
Language: | English |
Date of Publication (online): | 2021/09/06 |
Date of first Publication: | 2021/09/06 |
Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
Release Date: | 2022/02/09 |
Tag: | Cell biology; Genetics |
Volume: | 40 |
Page Number: | 10 |
First Page: | 6093 |
Last Page: | 6102 |
Note: | This work is funded by DFG grants Ma 1876/12-1 and Ma 1876/13-1, and grant 2018.070.1 and 2018.070.2 from the Wilhelm Sander Foundation. Open Access funding enabled and organized by Projekt DEAL. |
HeBIS-PPN: | 49209702X |
Institutes: | Biochemie, Chemie und Pharmazie |
Dewey Decimal Classification: | 5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie |
6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit | |
Sammlungen: | Universitätspublikationen |
Licence (German): | Creative Commons - Namensnennung 4.0 |