The role of reciprocal fusions in MLL-r acute leukemia: studying the chromosomal translocation t(4;11).
Chromatin Immunoprecipitation Sequencing
/ methods
Chromosomes, Human, Pair 11
/ genetics
Chromosomes, Human, Pair 4
/ genetics
Disease Progression
HEK293 Cells
Humans
Leukemia, Myeloid, Acute
/ genetics
Myeloid-Lymphoid Leukemia Protein
/ genetics
Oncogene Proteins, Fusion
/ genetics
Sequence Analysis, RNA
/ methods
Translocation, Genetic
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
10 2021
10 2021
Historique:
received:
16
03
2021
accepted:
20
08
2021
revised:
10
08
2021
pubmed:
8
9
2021
medline:
31
12
2021
entrez:
7
9
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34489550
doi: 10.1038/s41388-021-02001-2
pii: 10.1038/s41388-021-02001-2
pmc: PMC8530991
doi:
Substances chimiques
MLL-AF4 fusion protein, human
0
Oncogene Proteins, Fusion
0
Myeloid-Lymphoid Leukemia Protein
149025-06-9
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
6093-6102Informations de copyright
© 2021. The Author(s).
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