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

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:	Lin, Kuan-Ting Krainer, Adrian R.
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:	Publisher
URI:	https://repository.cshl.edu/id/eprint/37726

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