GSE264084 Depletion of ribosome biogenesis factors in NPM1-mutant acute myeloid leukemia: Insights into direct consequences of the mutation and implications for treatment

Contributors : Aristi Damaskou ; Rachael Wilson ; Malgorzata Gozdecka ; Muxin Gu ; Maria Eleftheriou ; Eliza Yankova ; Justyna Rak ; George S VassiliouSeries Type : Expression profiling by high throughput sequencingOrganism : Homo sapiensMutations in the NPM1 gene are found in more than 30% of acute myeloid leukemia (AML) cases. The mutations disrupt a nucleolar localization signal (NoLS) and create a novel nuclear export signal (NES), leading to cytoplasmic displacement of the protein (NPM1c). NPM1c mutations prime hematopoietic progenitors to leukemic transformation, but their precise molecular consequences remain elusive. Here, we first examined the effects of isolated NPM1c mutations on the global proteome of pre-leukemic hematopoietic progenitors using a conditional knock-in Npm1cA/+ mouse model. We discovered a significant depletion of many factors involved in the ribosome biogenesis pathway which, importantly, persists in NPM1-mutant AML patients. Next, we found that pre-leukemic Npm1cA/+ cells display higher sensitivity to Actinomycin D (ActD) and other RNA pol I inhibitors when compared to wild-type Npm1+/+ cells. Combination treatment with ActD and Venetoclax inhibited the growth and colony forming ability of pre-leukemic and leukemic NPM1c+ cells and low-dose ActD treatment was able to re-sensitize resistant NPM1c+ cells to Venetoclax. Finally, by contrasting our findings with data from CRISPR drop-out screens, we identified and validated TSR3, a ribosome ma...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by high throughput sequencing Homo sapiens Source Type: research