Targeting an RNA-binding protein network in acute myeloid leukemia Journal Article

Authors: Wang, E.; Lu, S. X.; Pastore, A.; Chen, X.; Imig, J.; Lee, S. C. W.; Hockemeyer, K.; Ghebrechristos, Y. E.; Yoshimi, A.; Inoue, D.; Ki, M.; Cho, H.; Bitner, L.; Kloetgen, A.; Lin, K. T.; Uehara, T.; Owa, T.; Tibes, R.; Krainer, A. R.; Abdel-Wahab, O.; Aifantis, I.
Article Title: Targeting an RNA-binding protein network in acute myeloid leukemia
Abstract: Using a CRISPR/Cas9 screen targeting RNA-binding domains of classical RNA-binding proteins (RBPs), Wang et al. uncover a network of interacting RBPs upregulated in acute myeloid leukemia (AML) and crucial for RNA splicing and AML survival, highlighting RBM39 as a central, targetable component of the RBP network. © 2019 Elsevier Inc. 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. © 2019 Elsevier Inc.
Keywords: cancer survival; clinical article; controlled study; leukemia; unclassified drug; human cell; exon; nonhuman; comparative study; proteome; animal cell; mouse; animal tissue; gene overexpression; apoptosis; gene expression; protein targeting; animal experiment; animal model; in vitro study; rna binding protein; rna-binding proteins; messenger rna; sulfonamides; leukemogenesis; alternative splicing; upregulation; spliceosome; ribosome rna; point mutation; genomic dna; rna splicing; gene cassette; aml; molecular pathology; transcription factor hoxa9; acute myeloid leukemia; next generation sequencing; human; male; priority journal; article; crispr; intron retention; crispr-cas9 system; dcaf15; rbm39; rna binding protein 39
Journal Title: Cancer Cell
Volume: 35
Issue: 3
ISSN: 1535-6108
Publisher: Cell Press  
Date Published: 2019-03-18
Start Page: 369
End Page: 384.e7
Language: English
DOI: 10.1016/j.ccell.2019.01.010
PUBMED: 30799057
PROVIDER: scopus
PMCID: PMC6424627
Notes: Source: Scopus
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MSK Authors
  1. Sydney X Lu
    51 Lu
  2. Stanley Chun-Wei Lee
    32 Lee
  3. Ha Na   Cho
    9 Cho
  4. Alessandro   Pastore
    28 Pastore
  5. Daichi   Inoue
    16 Inoue
  6. Akihide   Yoshimi
    25 Yoshimi
  7. Michelle Carmen Ki
    8 Ki
  8. Lillian Elizabeth Bitner
    6 Bitner