TY  - JOUR
A1  - Kundu, Arpita
A1  - Kowarz, Eric
A1  - Marschalek, Rolf
T1  - The role of reciprocal fusions in MLL-r acute leukemia: studying the chromosomal translocation t(6;11)
T2  - Oncogene
N2  - 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.
KW  - Cancer
KW  - Cell biology
Y1  - 2021
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/62617
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-626179
SN  - 1476-5594
N1  - 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.
N1  - Early View: Online Version before inclusion in an issue.
N1  - Version of Record: http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:hebis:30:3-633475
VL  - 2021
IS  - Early View: Online Version before inclusion in an issue
SP  - 1
EP  - 11
PB  - Springer Nature
CY  - London
ER  -