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 > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > Alternative Splicing
diseases & disorders > cancer > cancer types > leukemia
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > RNA binding protein
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > spliceosome complex
CSHL Authors:
Communities: CSHL labs > Krainer lab
Depositing User: Matthew Dunn
Date: 4 February 2019
Date Deposited: 04 Mar 2019 20:11
Last Modified: 09 Apr 2019 16:36
Related URLs:
URI: http://repository.cshl.edu/id/eprint/37726

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