Targeting an RNA-Binding Protein Network in Acute Myeloid Leukemia

Highlights

• CRISPR/Cas9 domain screen reveals RBP dependencies in AML

• RBM39 is required for AML maintenance through mis-splicing of HOXA9 target genes

• Proteomic studies identify an essential RBP splicing network in AML

• Pharmacologic RBM39 degradation leads to broad anti-leukemic effects

Summary

RNA-binding proteins (RBPs) are essential modulators of transcription and translation frequently dysregulated in cancer. We systematically interrogated RBP dependencies in human cancers using a comprehensive CRISPR/Cas9 domain-focused screen targeting RNA-binding domains of 490 classical RBPs. This uncovered a network of physically interacting RBPs upregulated in acute myeloid leukemia (AML) and crucial for maintaining RNA splicing and AML survival. Genetic or pharmacologic targeting of one key member of this network, RBM39, repressed cassette exon inclusion and promoted intron retention within mRNAs encoding HOXA9 targets as well as in other RBPs preferentially required in AML. The effects of RBM39 loss on splicing further resulted in preferential lethality of spliceosomal mutant AML, providing a strategy for treatment of AML bearing RBP splicing mutations.