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 Akashi; Daniel E. Bauer; Takahiro Maeda

doi:10.1016/j.ccell.2018.01.012

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^*

^*Corresponding author for this work

Bioscience

Research output: Contribution to journal › Article › peer-review

88 Scopus citations

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.

Original language	English (US)
Pages (from-to)	386-400.e5
Journal	Cancer Cell
Volume	33
Issue number	3
DOIs	https://doi.org/10.1016/j.ccell.2018.01.012
State	Published - Mar 12 2018

Bibliographical note

Funding Information:
We thank Hai Yi, Catherine Zhu, and members in the Division of Hematology at BWH and Department of Medicine and Biosystemic Science at Kyushu University for assistance, advice, and helpful discussion, Zach Herbert for help and advice on sequencing and Elise Lamar for critical reading of the manuscript. This work is supported in part by a Grant-in-Aid for JSPS Fellows ( 15J10130 ) (to T.Y.), an NIDDK Predoctoral National Research Service Award for an MD/PhD Fellowship ( F30DK103359-01A1 ) (to M.C.C.), a JSPS Young Researcher Overseas Visits Program for Vitalizing Brain Circulation Fellowship (to Y.I.), a Strategic Positioning Fund for Genetic Orphan Diseases from the Agency for Science, Technology, and Research in Singapore (to B.R.), NIH R00HG008399 (to L.P.), NIDDK ( K08DK093705 , R03DK109232 ), NHLBI ( DP2OD022716 ), Burroughs Wellcome Fund , and American Society of Hematology (to D.E.B.), NIH P01HL032262 and P30DK049216 grants (Center of Excellence in Molecular Hematology) (to S.H.O.), a JSPS Grant-in-Aid for Scientific Research (S) ( 16H06391 ) (to K.A.), and a JSPS Grant-in-Aid for Scientific Research (A) ( 17H01567 ), American Cancer Society ( RSG-13-379-01-LIB ) and an American Society of Hematology Bridge Grant (to T.M.).

Publisher Copyright:
© 2018 Elsevier Inc.

Keywords

acute myeloid leukemia
CRISPR-Cas9 saturation mutagenesis
decapping enzyme
drug repurposing
genome-wide CRISPR-Cas9 screening
mRNA decay
pre-mRNA metabolism
pre-mRNA splicing

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ccell.2018.01.012

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Yamauchi, T., Masuda, T., Canver, M. C., Seiler, M., Semba, Y., Shboul, M., Al-Raqad, M., Maeda, M., Schoonenberg, V. A. C., Cole, M. A., Macias-Trevino, C., Ishikawa, Y., Yao, Q., Nakano, M., Arai, F., Orkin, S. H., Reversade, B., Buonamici, S., Pinello, L., ... Maeda, T. (2018). Genome-wide CRISPR-Cas9 Screen Identifies Leukemia-Specific Dependence on a Pre-mRNA Metabolic Pathway Regulated by DCPS. Cancer Cell, 33(3), 386-400.e5. https://doi.org/10.1016/j.ccell.2018.01.012

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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.",

keywords = "acute myeloid leukemia, CRISPR-Cas9 saturation mutagenesis, decapping enzyme, drug repurposing, genome-wide CRISPR-Cas9 screening, mRNA decay, pre-mRNA metabolism, pre-mRNA splicing",

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",

note = "Funding Information: We thank Hai Yi, Catherine Zhu, and members in the Division of Hematology at BWH and Department of Medicine and Biosystemic Science at Kyushu University for assistance, advice, and helpful discussion, Zach Herbert for help and advice on sequencing and Elise Lamar for critical reading of the manuscript. This work is supported in part by a Grant-in-Aid for JSPS Fellows ( 15J10130 ) (to T.Y.), an NIDDK Predoctoral National Research Service Award for an MD/PhD Fellowship ( F30DK103359-01A1 ) (to M.C.C.), a JSPS Young Researcher Overseas Visits Program for Vitalizing Brain Circulation Fellowship (to Y.I.), a Strategic Positioning Fund for Genetic Orphan Diseases from the Agency for Science, Technology, and Research in Singapore (to B.R.), NIH R00HG008399 (to L.P.), NIDDK ( K08DK093705 , R03DK109232 ), NHLBI ( DP2OD022716 ), Burroughs Wellcome Fund , and American Society of Hematology (to D.E.B.), NIH P01HL032262 and P30DK049216 grants (Center of Excellence in Molecular Hematology) (to S.H.O.), a JSPS Grant-in-Aid for Scientific Research (S) ( 16H06391 ) (to K.A.), and a JSPS Grant-in-Aid for Scientific Research (A) ( 17H01567 ), American Cancer Society ( RSG-13-379-01-LIB ) and an American Society of Hematology Bridge Grant (to T.M.). Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",

year = "2018",

month = mar,

day = "12",

doi = "10.1016/j.ccell.2018.01.012",

language = "English (US)",

volume = "33",

pages = "386--400.e5",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "3",

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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, vol. 33, no. 3, pp. 386-400.e5. https://doi.org/10.1016/j.ccell.2018.01.012

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

N1 - Funding Information: We thank Hai Yi, Catherine Zhu, and members in the Division of Hematology at BWH and Department of Medicine and Biosystemic Science at Kyushu University for assistance, advice, and helpful discussion, Zach Herbert for help and advice on sequencing and Elise Lamar for critical reading of the manuscript. This work is supported in part by a Grant-in-Aid for JSPS Fellows ( 15J10130 ) (to T.Y.), an NIDDK Predoctoral National Research Service Award for an MD/PhD Fellowship ( F30DK103359-01A1 ) (to M.C.C.), a JSPS Young Researcher Overseas Visits Program for Vitalizing Brain Circulation Fellowship (to Y.I.), a Strategic Positioning Fund for Genetic Orphan Diseases from the Agency for Science, Technology, and Research in Singapore (to B.R.), NIH R00HG008399 (to L.P.), NIDDK ( K08DK093705 , R03DK109232 ), NHLBI ( DP2OD022716 ), Burroughs Wellcome Fund , and American Society of Hematology (to D.E.B.), NIH P01HL032262 and P30DK049216 grants (Center of Excellence in Molecular Hematology) (to S.H.O.), a JSPS Grant-in-Aid for Scientific Research (S) ( 16H06391 ) (to K.A.), and a JSPS Grant-in-Aid for Scientific Research (A) ( 17H01567 ), American Cancer Society ( RSG-13-379-01-LIB ) and an American Society of Hematology Bridge Grant (to T.M.). Publisher Copyright: © 2018 Elsevier Inc.

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.

KW - acute myeloid leukemia

KW - CRISPR-Cas9 saturation mutagenesis

KW - decapping enzyme

KW - drug repurposing

KW - genome-wide CRISPR-Cas9 screening

KW - mRNA decay

KW - pre-mRNA metabolism

KW - pre-mRNA splicing

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U2 - 10.1016/j.ccell.2018.01.012

DO - 10.1016/j.ccell.2018.01.012

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AN - SCOPUS:85042837062

SN - 1535-6108

VL - 33

SP - 386-400.e5

JO - Cancer Cell

JF - Cancer Cell

IS - 3

ER -

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

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