The role of reciprocal fusions in MLL-r acute leukemia: studying the chromosomal translocation t(6;11).
Arpita KunduEric KowarzRolf MarschalekPublished in: Oncogene (2021)
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.
Keyphrases
- acute myeloid leukemia
- atrial fibrillation
- genome wide
- gene expression
- dna methylation
- rna seq
- protein protein
- copy number
- single cell
- allogeneic hematopoietic stem cell transplantation
- genome wide identification
- newly diagnosed
- bone marrow
- immune response
- chronic kidney disease
- ejection fraction
- oxidative stress
- amino acid
- genome wide analysis
- heat shock