Targeting an RNA-Binding Protein Network in Acute Myeloid Leukemia

Wang, E., Lu, S. X., Pastore, A., Chen, X., Imig, J., Chun-Wei Lee, S., 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. (February 2019) Targeting an RNA-Binding Protein Network in Acute Myeloid Leukemia. Cancer Cell, 35 (3). 359-384.e7. ISSN 1535-6108

URL: https://www.ncbi.nlm.nih.gov/pubmed/30799057
DOI: 10.1016/j.ccell.2019.01.010

Abstract

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.

Item Type: Paper
Subjects: bioinformatics
diseases & disorders > cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification
diseases & disorders
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
Investigative techniques and equipment
diseases & disorders > neoplasms
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification
diseases & disorders > cancer > cancer types > acute myeloid leukemia
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > Alternative Splicing
organism description > animal
Investigative techniques and equipment > CRISPR-Cas9
diseases & disorders > cancer > cancer types > leukemia
organism description > animal > mammal
organism description > animal > mammal > rodent > mouse
diseases & disorders > cancer > prognosis
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > RNA binding protein
organism description > animal > mammal > rodent
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > spliceosome complex
diseases & disorders > cancer > cancer types
CSHL Authors:
Communities: CSHL labs > Krainer lab
CSHL Cancer Center Program > Gene Regulation and Inheritance Program
Depositing User: Matthew Dunn
Date: 4 February 2019
Date Deposited: 04 Mar 2019 20:11
Last Modified: 05 Feb 2024 20:55
PMCID: PMC6424627
Related URLs:
URI: https://repository.cshl.edu/id/eprint/37726

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