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 |
| DOI/URL: | |
| Notes: | Source: Scopus |
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