GSE114558 Targeting an RNA-binding Protein Splicing Network in Acute Myeloid Leukemia

Contributors : Eric Wang ; Alessandro Pastore ; Sydney X Lu ; Xufeng Chen ; Jochen Imig ; Yohana E Ghebrechristos ; Akihide Yoshimi ; Lillian Bitner ; Andreas Kloetgen ; Kuan-Ting Lin ; Taisuke Uehara ; Takashi Owa ; Raoul Tibes ; Adrian R Krainer ; Omar Abdel-Wahab ; Iannis AifantisSeries Type : Expression profiling by high throughput sequencingOrganism : Homo sapiensRNA-binding proteins (RBPs) are essential modulators of transcription and translation and are often dysregulated in cancer. Here we systematically interrogated RBP vulnerabilities in acute myeloid leukemia (AML) by performing a comprehensive CRISPR/Cas9 screen, targeting the RNA-binding domains of all classical RBPs. Our screen revealed RBPs that are exclusively required for leukemia survival, including the splicing factor RBM39. Proteomics analysis identified a network of RBP ’s interacting with RBM39 crucial for maintaining RNA splicing and survival in AML. Mechanistically, RBM39 suppression led to altered splicing of genes involved in essential oncogenic pathways. Selective targeting of RBM39 via ubiquitin-mediated pharmacologic degradation induced broad anti-leukemi c effects in vitro and potent single agent activity in vivo. The effects of RBM39 loss on alteration of splicing further resulted in preferential lethality of AML cells bearing spliceosomal gene mutations, thereby providing a strategy for treating AML patients bearing RBP splicing mutations.
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by high throughput sequencing Homo sapiens Source Type: research