Targeting an RNA-Binding Protein Network in Acute Myeloid Leukemia.
Alternative Splicing
Animals
CRISPR-Cas Systems
Cell Line, Tumor
Female
Gene Expression Regulation, Neoplastic
Gene Regulatory Networks
Gene Targeting
/ methods
HL-60 Cells
Homeodomain Proteins
/ genetics
Humans
Jurkat Cells
Leukemia, Myeloid, Acute
/ genetics
Male
Mice
Neoplasm Transplantation
Prognosis
Proteomics
/ methods
RNA-Binding Proteins
/ genetics
Sequence Analysis, RNA
/ methods
Survival Analysis
Up-Regulation
AML
CRISPR
DCAF15
RBM39
RNA-binding proteins
alternative splicing
leukemia
spliceosome
sulfonamides
Journal
Cancer cell
ISSN: 1878-3686
Titre abrégé: Cancer Cell
Pays: United States
ID NLM: 101130617
Informations de publication
Date de publication:
18 03 2019
18 03 2019
Historique:
received:
02
07
2018
revised:
26
11
2018
accepted:
18
01
2019
pubmed:
26
2
2019
medline:
24
12
2019
entrez:
26
2
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 30799057
pii: S1535-6108(19)30044-3
doi: 10.1016/j.ccell.2019.01.010
pmc: PMC6424627
mid: NIHMS1520966
pii:
doi:
Substances chimiques
HCC1 autoantigen
0
Homeodomain Proteins
0
RNA-Binding Proteins
0
homeobox protein HOXA9
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
369-384.e7Subventions
Organisme : NCI NIH HHS
ID : R01 CA173636
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA016087
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA194923
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA228135
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL128239
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA216421
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA169784
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA013106
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.
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