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
Parent Title (English):Oncogene
Publisher:Springer Nature
Place of publication:London
Document Type:Article
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
Page Number:10
First Page:6093
Last Page:6102
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.
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
Licence (German):License LogoCreative Commons - Namensnennung 4.0