Targeting an RNA-Binding Protein Network in Acute Myeloid Leukemia

Cancer Cell. 2019 Mar 18;35(3):369-384.e7. doi: 10.1016/j.ccell.2019.01.010. Epub 2019 Feb 21.


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.

Keywords: AML; CRISPR; DCAF15; RBM39; RNA-binding proteins; alternative splicing; leukemia; spliceosome; sulfonamides.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alternative Splicing
  • Animals
  • CRISPR-Cas Systems
  • Cell Line, Tumor
  • Female
  • Gene Expression Regulation, Neoplastic
  • Gene Regulatory Networks*
  • Gene Targeting / methods*
  • HL-60 Cells
  • Homeodomain Proteins / genetics
  • Humans
  • Jurkat Cells
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / metabolism
  • Leukemia, Myeloid, Acute / pathology*
  • Male
  • Mice
  • Neoplasm Transplantation
  • Prognosis
  • Proteomics / methods*
  • RNA-Binding Proteins / genetics*
  • RNA-Binding Proteins / metabolism
  • Sequence Analysis, RNA / methods
  • Survival Analysis
  • Up-Regulation*


  • HCC1 autoantigen
  • Homeodomain Proteins
  • RNA-Binding Proteins
  • homeobox protein HOXA9