GSE118963 The p30 isoform of CEBPA uncovers a silent enhancer to drive the expression of the tumor promotive factor CD73 in CEBPA mutant AML

Contributors : Janus S Jakobsen ; Linea G Laursen ; Mikkel B Schuster ; Sachin Pundhir ; Nicolas Rapin ; Erwin Schoof ; Ying Ge ; Kristoffer Vitting-Seerup ; Coline Gentil ; Johan Jendholm ; Peter Hokland ; Jude Fitzgibbon ; Bo T PorseSeries Type : Expression profiling by high throughput sequencing ; Genome binding/occupancy profiling by high throughput sequencingOrganism : Homo sapiens ; Mus musculusCEBPA is a key hematopoietic transcription factor (TF), found mutated in 5-14% of all acute myeloid leukemia (AML) cases, but the direct molecular ramifications of this driver mutation remains elusive. To investigate CEBPA-mutant AML, we compared patient aberrant genetic programs with changes in a precise mouse model (Lp30) expressing only the cancer-prevalent truncated CEBPA, p30, and identified a stringent cross-species AML program. Small-scale ChIP-seq methodology revealed aberrantly activated enhancers, exclusively occupied by CEBPA in leukemia. One cancer-enhancer upstream of Nt5e, encoding CD73, was physically and functionally linked to this conserved AML gene, and could be activated by CEBPA. Targeting of CD73-adenosine signaling increased survival in AML transplanted mice. Our data thus indicate a first-in-class link between a TF cancer driver mutation and a druggable, direct transcriptional target.
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by high throughput sequencing Genome binding/occupancy profiling by high throughput sequencing Homo sapiens Mus musculus Source Type: research