Genome-wide CRISPR-Cas9 Screen Identifies Leukemia-Specific Dependence on a Pre-mRNA Metabolic Pathway Regulated by DCPS

takuji yamauchi, Takeshi Masuda, Matthew C. Canver, Michael Seiler, Yuichiro Semba, Mohammad Shboul, Mohammed Al-Raqad, Manami Maeda, Vivien A.C. Schoonenberg, Mitchel A. Cole, Claudio Macias-Trevino, Yuichi Ishikawa, Qiuming Yao, Michitaka Nakano, Fumio Arai, Stuart H. Orkin, Bruno Reversade, Silvia Buonamici, Luca Pinello, Koichi AkashiDaniel E. Bauer, Takahiro Maeda

研究成果: ジャーナルへの寄稿記事

15 引用 (Scopus)

抄録

To identify novel targets for acute myeloid leukemia (AML) therapy, we performed genome-wide CRISPR-Cas9 screening using AML cell lines, followed by a second screen in vivo. Here, we show that the mRNA decapping enzyme scavenger (DCPS) gene is essential for AML cell survival. The DCPS enzyme interacted with components of pre-mRNA metabolic pathways, including spliceosomes, as revealed by mass spectrometry. RG3039, a DCPS inhibitor originally developed to treat spinal muscular atrophy, exhibited anti-leukemic activity via inducing pre-mRNA mis-splicing. Humans harboring germline biallelic DCPS loss-of-function mutations do not exhibit aberrant hematologic phenotypes, indicating that DCPS is dispensable for human hematopoiesis. Our findings shed light on a pre-mRNA metabolic pathway and identify DCPS as a target for AML therapy. Yamauchi et al. perform in vitro and in vivo CRISPR-Cas9 genetic screening of p53 WT AML to identify potential therapeutic targets. They find that AML relies on the DCPS decapping enzyme, and a DCPS inhibitor shows anti-leukemia activity in tumor models without impacting normal hematopoiesis.

元の言語英語
ページ(範囲)386-400.e5
ジャーナルCancer Cell
33
発行部数3
DOI
出版物ステータス出版済み - 3 12 2018

Fingerprint

Clustered Regularly Interspaced Short Palindromic Repeats
RNA Precursors
Metabolic Networks and Pathways
Leukemia
Genome
Acute Myeloid Leukemia
Hematopoiesis
Enzyme Inhibitors
Myeloid Cells
Spliceosomes
mRNA decapping enzymes
Spinal Muscular Atrophy
Essential Genes
Genetic Testing
Mass Spectrometry
Cell Survival
Therapeutics

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cell Biology
  • Cancer Research

これを引用

Genome-wide CRISPR-Cas9 Screen Identifies Leukemia-Specific Dependence on a Pre-mRNA Metabolic Pathway Regulated by DCPS. / yamauchi, takuji; Masuda, Takeshi; Canver, Matthew C.; Seiler, Michael; Semba, Yuichiro; Shboul, Mohammad; Al-Raqad, Mohammed; Maeda, Manami; Schoonenberg, Vivien A.C.; Cole, Mitchel A.; Macias-Trevino, Claudio; Ishikawa, Yuichi; Yao, Qiuming; Nakano, Michitaka; Arai, Fumio; Orkin, Stuart H.; Reversade, Bruno; Buonamici, Silvia; Pinello, Luca; Akashi, Koichi; Bauer, Daniel E.; Maeda, Takahiro.

:: Cancer Cell, 巻 33, 番号 3, 12.03.2018, p. 386-400.e5.

研究成果: ジャーナルへの寄稿記事

yamauchi, T, Masuda, T, Canver, MC, Seiler, M, Semba, Y, Shboul, M, Al-Raqad, M, Maeda, M, Schoonenberg, VAC, Cole, MA, Macias-Trevino, C, Ishikawa, Y, Yao, Q, Nakano, M, Arai, F, Orkin, SH, Reversade, B, Buonamici, S, Pinello, L, Akashi, K, Bauer, DE & Maeda, T 2018, 'Genome-wide CRISPR-Cas9 Screen Identifies Leukemia-Specific Dependence on a Pre-mRNA Metabolic Pathway Regulated by DCPS', Cancer Cell, 巻. 33, 番号 3, pp. 386-400.e5. https://doi.org/10.1016/j.ccell.2018.01.012
yamauchi, takuji ; Masuda, Takeshi ; Canver, Matthew C. ; Seiler, Michael ; Semba, Yuichiro ; Shboul, Mohammad ; Al-Raqad, Mohammed ; Maeda, Manami ; Schoonenberg, Vivien A.C. ; Cole, Mitchel A. ; Macias-Trevino, Claudio ; Ishikawa, Yuichi ; Yao, Qiuming ; Nakano, Michitaka ; Arai, Fumio ; Orkin, Stuart H. ; Reversade, Bruno ; Buonamici, Silvia ; Pinello, Luca ; Akashi, Koichi ; Bauer, Daniel E. ; Maeda, Takahiro. / Genome-wide CRISPR-Cas9 Screen Identifies Leukemia-Specific Dependence on a Pre-mRNA Metabolic Pathway Regulated by DCPS. :: Cancer Cell. 2018 ; 巻 33, 番号 3. pp. 386-400.e5.
@article{cbc699fc4d88429bb14386066902da56,
title = "Genome-wide CRISPR-Cas9 Screen Identifies Leukemia-Specific Dependence on a Pre-mRNA Metabolic Pathway Regulated by DCPS",
abstract = "To identify novel targets for acute myeloid leukemia (AML) therapy, we performed genome-wide CRISPR-Cas9 screening using AML cell lines, followed by a second screen in vivo. Here, we show that the mRNA decapping enzyme scavenger (DCPS) gene is essential for AML cell survival. The DCPS enzyme interacted with components of pre-mRNA metabolic pathways, including spliceosomes, as revealed by mass spectrometry. RG3039, a DCPS inhibitor originally developed to treat spinal muscular atrophy, exhibited anti-leukemic activity via inducing pre-mRNA mis-splicing. Humans harboring germline biallelic DCPS loss-of-function mutations do not exhibit aberrant hematologic phenotypes, indicating that DCPS is dispensable for human hematopoiesis. Our findings shed light on a pre-mRNA metabolic pathway and identify DCPS as a target for AML therapy. Yamauchi et al. perform in vitro and in vivo CRISPR-Cas9 genetic screening of p53 WT AML to identify potential therapeutic targets. They find that AML relies on the DCPS decapping enzyme, and a DCPS inhibitor shows anti-leukemia activity in tumor models without impacting normal hematopoiesis.",
author = "takuji yamauchi and Takeshi Masuda and Canver, {Matthew C.} and Michael Seiler and Yuichiro Semba and Mohammad Shboul and Mohammed Al-Raqad and Manami Maeda and Schoonenberg, {Vivien A.C.} and Cole, {Mitchel A.} and Claudio Macias-Trevino and Yuichi Ishikawa and Qiuming Yao and Michitaka Nakano and Fumio Arai and Orkin, {Stuart H.} and Bruno Reversade and Silvia Buonamici and Luca Pinello and Koichi Akashi and Bauer, {Daniel E.} and Takahiro Maeda",
year = "2018",
month = "3",
day = "12",
doi = "10.1016/j.ccell.2018.01.012",
language = "English",
volume = "33",
pages = "386--400.e5",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "3",

}

TY - JOUR

T1 - Genome-wide CRISPR-Cas9 Screen Identifies Leukemia-Specific Dependence on a Pre-mRNA Metabolic Pathway Regulated by DCPS

AU - yamauchi, takuji

AU - Masuda, Takeshi

AU - Canver, Matthew C.

AU - Seiler, Michael

AU - Semba, Yuichiro

AU - Shboul, Mohammad

AU - Al-Raqad, Mohammed

AU - Maeda, Manami

AU - Schoonenberg, Vivien A.C.

AU - Cole, Mitchel A.

AU - Macias-Trevino, Claudio

AU - Ishikawa, Yuichi

AU - Yao, Qiuming

AU - Nakano, Michitaka

AU - Arai, Fumio

AU - Orkin, Stuart H.

AU - Reversade, Bruno

AU - Buonamici, Silvia

AU - Pinello, Luca

AU - Akashi, Koichi

AU - Bauer, Daniel E.

AU - Maeda, Takahiro

PY - 2018/3/12

Y1 - 2018/3/12

N2 - To identify novel targets for acute myeloid leukemia (AML) therapy, we performed genome-wide CRISPR-Cas9 screening using AML cell lines, followed by a second screen in vivo. Here, we show that the mRNA decapping enzyme scavenger (DCPS) gene is essential for AML cell survival. The DCPS enzyme interacted with components of pre-mRNA metabolic pathways, including spliceosomes, as revealed by mass spectrometry. RG3039, a DCPS inhibitor originally developed to treat spinal muscular atrophy, exhibited anti-leukemic activity via inducing pre-mRNA mis-splicing. Humans harboring germline biallelic DCPS loss-of-function mutations do not exhibit aberrant hematologic phenotypes, indicating that DCPS is dispensable for human hematopoiesis. Our findings shed light on a pre-mRNA metabolic pathway and identify DCPS as a target for AML therapy. Yamauchi et al. perform in vitro and in vivo CRISPR-Cas9 genetic screening of p53 WT AML to identify potential therapeutic targets. They find that AML relies on the DCPS decapping enzyme, and a DCPS inhibitor shows anti-leukemia activity in tumor models without impacting normal hematopoiesis.

AB - To identify novel targets for acute myeloid leukemia (AML) therapy, we performed genome-wide CRISPR-Cas9 screening using AML cell lines, followed by a second screen in vivo. Here, we show that the mRNA decapping enzyme scavenger (DCPS) gene is essential for AML cell survival. The DCPS enzyme interacted with components of pre-mRNA metabolic pathways, including spliceosomes, as revealed by mass spectrometry. RG3039, a DCPS inhibitor originally developed to treat spinal muscular atrophy, exhibited anti-leukemic activity via inducing pre-mRNA mis-splicing. Humans harboring germline biallelic DCPS loss-of-function mutations do not exhibit aberrant hematologic phenotypes, indicating that DCPS is dispensable for human hematopoiesis. Our findings shed light on a pre-mRNA metabolic pathway and identify DCPS as a target for AML therapy. Yamauchi et al. perform in vitro and in vivo CRISPR-Cas9 genetic screening of p53 WT AML to identify potential therapeutic targets. They find that AML relies on the DCPS decapping enzyme, and a DCPS inhibitor shows anti-leukemia activity in tumor models without impacting normal hematopoiesis.

UR - http://www.scopus.com/inward/record.url?scp=85042837062&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85042837062&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2018.01.012

DO - 10.1016/j.ccell.2018.01.012

M3 - Article

C2 - 29478914

AN - SCOPUS:85042837062

VL - 33

SP - 386-400.e5

JO - Cancer Cell

JF - Cancer Cell

SN - 1535-6108

IS - 3

ER -