GSE239469 Condensate-promoting ENL mutation induces tumorigenesis via chromatin remodeling [RNA-seq]

Contributors : Liling Wan ; Yiman Liu ; Qinglan LiSeries Type : Expression profiling by high throughput sequencingOrganism : Mus musculusGain-of-function mutations in the chromatin ‘reader’ ENL, identified in AML and Wilms tumor, have been shown to induce aberrant formation of transcriptional condensates in cellular systems. However, the precise role of these mutations and their condensate forming property in tumorigenesis remains unclear. By creating a conditional knock-i n mouse model for the most prevalent ENL mutation, we establish ENL mutant as a bona fide oncogenic driver of acute myeloid leukemia in vivo. Heterozygous expression of ENL mutant perturbs the normal hematopoietic hierarchy and results in the aberrant expansion of myeloid progenitors with increased self-renewal property. Furthermore, the ENL mutant remodels histone modifications to alter differentiation processes and drive oncogenic gene expression during hematopoietic development. Importantly, targeted point mutagenesis to disrupt the condensate formation property completely abolishes ENL mut ant’s oncogenic function in hematopoietic stem and progenitor cells (HSPCs). Lastly, short-term treatment with a small molecule inhibitor that blocks the acetyl-binding activity of ENL mutant reverts its impact on chromatin and significantly delays leukemia development in mice. Our studies reveal the crucial biological function of mutation-induced transcriptional condensates in chromatin regulation and cancer...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by high throughput sequencing Mus musculus Source Type: research