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

RNA-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-leukemic 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. The goals of this project are to investigaet the role of RBM39 degradation in AML