The role of reciprocal fusions in MLL-r acute leukemia: studying the chromosomal translocation t(6;11)
- Leukemia patients bearing t(6;11)(q27;q23) translocations can be divided in two subgroups: those with breakpoints in the major breakpoint cluster region of MLL (introns 9–10; associated mainly with AML M1/4/5), and others with breakpoints in the minor breakpoint cluster region (introns 21–23), associated with T-ALL. We cloned all four of the resulting fusion genes (MLL-AF6, AF6-MLL, exMLL-AF6, AF6-shMLL) and subsequently transfected them to generate stable cell culture models. Their molecular function was tested by inducing gene expression for 48 h in a Doxycycline-dependent fashion. Here, we present our results upon differential gene expression (DGE) that were obtained by the “Massive Analyses of cDNA Ends” (MACE-Seq) technology, an established 3′-end based RNA-Seq method. Our results indicate that the PHD/BD domain, present in the AF6-MLL and the exMLL-AF6 fusion protein, is responsible for chromatin activation in a genome-wide fashion. This led to strong deregulation of transcriptional processes involving protein-coding genes, pseudogenes, non-annotated genes, and RNA genes, e.g., LincRNAs and microRNAs, respectively. While cooperation between the MLL-AF6 and AF6-MLL fusion proteins appears to be required for the above-mentioned effects, exMLL-AF6 is able to cause similar effects on its own. The exMLL-AF6/AF6-shMLL co-expressing cell line displayed the induction of a myeloid-specific and a T-cell specific gene signature, which may explain the T-ALL disease phenotype observed in patients with such breakpoints. This again demonstrated that MLL fusion proteins are instructive and allow to study their pathomolecular mechanisms.
Verfasserangaben: | Arpita KunduGND, Eric KowarzORCiDGND, Rolf MarschalekORCiDGND |
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URN: | urn:nbn:de:hebis:30:3-626179 |
DOI: | https://doi.org/10.1038/s41388-021-01983-3 |
ISSN: | 1476-5594 |
Titel des übergeordneten Werkes (Englisch): | Oncogene |
Verlag: | Springer Nature |
Verlagsort: | London |
Dokumentart: | Wissenschaftlicher Artikel |
Sprache: | Englisch |
Datum der Veröffentlichung (online): | 05.08.2021 |
Datum der Erstveröffentlichung: | 05.08.2021 |
Veröffentlichende Institution: | Universitätsbibliothek Johann Christian Senckenberg |
Datum der Freischaltung: | 18.10.2021 |
Freies Schlagwort / Tag: | Cancer; Cell biology |
Jahrgang: | 2021 |
Ausgabe / Heft: | Early View: Online Version before inclusion in an issue |
Seitenzahl: | 11 |
Erste Seite: | 1 |
Letzte Seite: | 11 |
Bemerkung: | This work is funded by DFG grants Ma 1876/12-1 and Ma 1876/13-1, and grants 2018.070.1 and 2018.070.2 from the Wilhelm Sander foundation. Open Access funding enabled and organized by Projekt DEAL. |
Bemerkung: | Early View: Online Version before inclusion in an issue. |
Bemerkung: | Version of Record: http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:hebis:30:3-633475 |
HeBIS-PPN: | 488130239 |
Institute: | Biochemie, Chemie und Pharmazie |
DDC-Klassifikation: | 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 |
Lizenz (Deutsch): | Creative Commons - Namensnennung 4.0 |