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Cancer Cell. 2019 Mar 18;35(3):369-384.e7. doi: 10.1016/j.ccell.2019.01.010. Epub 2019 Feb 21.

Targeting an RNA-Binding Protein Network in Acute Myeloid Leukemia.

Author information

1
Department of Pathology and Laura & Isaac Perlmutter Cancer Center, NYU School of Medicine, New York, NY 10016, USA.
2
Human Oncology and Pathogenesis Program and Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
3
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
4
Tsukuba Research Laboratories, Eisai Company, Ltd, Tsukuba, Ibaraki 300-4352, Japan.
5
Human Oncology and Pathogenesis Program and Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: abdelwao@mskcc.org.
6
Department of Pathology and Laura & Isaac Perlmutter Cancer Center, NYU School of Medicine, New York, NY 10016, USA. Electronic address: iannis.aifantis@nyumc.org.

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.

KEYWORDS:

AML; CRISPR; DCAF15; RBM39; RNA-binding proteins; alternative splicing; leukemia; spliceosome; sulfonamides

PMID:
30799057
PMCID:
PMC6424627
[Available on 2020-03-18]
DOI:
10.1016/j.ccell.2019.01.010

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