PRMT5 methylome profiling uncovers a direct link to splicing regulation in acute myeloid leukemia

Aliaksandra Radzisheuskaya; Pavel V Shliaha; Vasily Grinev; Eugenia Lorenzini; Sergey Kovalchuk; Daria Shlyueva; Vladimir Gorshkov; Ronald C Hendrickson; Ole N Jensen; Kristian Helin

doi:10.1038/s41594-019-0313-z

PRMT5 methylome profiling uncovers a direct link to splicing regulation in acute myeloid leukemia

Aliaksandra Radzisheuskaya, Pavel V Shliaha, Vasily Grinev, Eugenia Lorenzini, Sergey Kovalchuk, Daria Shlyueva, Vladimir Gorshkov, Ronald C Hendrickson, Ole N Jensen, Kristian Helin

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29 Citationer (Scopus)

Abstract

Protein arginine methyltransferase 5 (PRMT5) has emerged as a promising cancer drug target, and three PRMT5 inhibitors are currently in clinical trials for multiple malignancies. In this study, we investigated the role of PRMT5 in human acute myeloid leukemia (AML). Using an enzymatic dead version of PRMT5 and a PRMT5-specific inhibitor, we demonstrated the requirement of the catalytic activity of PRMT5 for the survival of AML cells. We then identified PRMT5 substrates using multiplexed quantitative proteomics and investigated their role in the survival of AML cells. We found that the function of the splicing regulator SRSF1 relies on its methylation by PRMT5 and that loss of PRMT5 leads to changes in alternative splicing of multiple essential genes. Our study proposes a mechanism for the requirement of PRMT5 for leukemia cell survival and provides potential biomarkers for the treatment response to PRMT5 inhibitors.

Originalsprog	Engelsk
Tidsskrift	Nature Structural & Molecular Biology
Vol/bind	26
Udgave nummer	11
Sider (fra-til)	999-1012
Antal sider	12
ISSN	1545-9993
DOI	https://doi.org/10.1038/s41594-019-0313-z
Status	Udgivet - 1 nov. 2019

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title = "PRMT5 methylome profiling uncovers a direct link to splicing regulation in acute myeloid leukemia",

abstract = "Protein arginine methyltransferase 5 (PRMT5) has emerged as a promising cancer drug target, and three PRMT5 inhibitors are currently in clinical trials for multiple malignancies. In this study, we investigated the role of PRMT5 in human acute myeloid leukemia (AML). Using an enzymatic dead version of PRMT5 and a PRMT5-specific inhibitor, we demonstrated the requirement of the catalytic activity of PRMT5 for the survival of AML cells. We then identified PRMT5 substrates using multiplexed quantitative proteomics and investigated their role in the survival of AML cells. We found that the function of the splicing regulator SRSF1 relies on its methylation by PRMT5 and that loss of PRMT5 leads to changes in alternative splicing of multiple essential genes. Our study proposes a mechanism for the requirement of PRMT5 for leukemia cell survival and provides potential biomarkers for the treatment response to PRMT5 inhibitors.",

author = "Aliaksandra Radzisheuskaya and Shliaha, {Pavel V} and Vasily Grinev and Eugenia Lorenzini and Sergey Kovalchuk and Daria Shlyueva and Vladimir Gorshkov and Hendrickson, {Ronald C} and Jensen, {Ole N} and Kristian Helin",

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doi = "10.1038/s41594-019-0313-z",

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T1 - PRMT5 methylome profiling uncovers a direct link to splicing regulation in acute myeloid leukemia

AU - Radzisheuskaya, Aliaksandra

AU - Shliaha, Pavel V

AU - Grinev, Vasily

AU - Lorenzini, Eugenia

AU - Kovalchuk, Sergey

AU - Shlyueva, Daria

AU - Gorshkov, Vladimir

AU - Hendrickson, Ronald C

AU - Jensen, Ole N

AU - Helin, Kristian

PY - 2019/11/1

Y1 - 2019/11/1

N2 - Protein arginine methyltransferase 5 (PRMT5) has emerged as a promising cancer drug target, and three PRMT5 inhibitors are currently in clinical trials for multiple malignancies. In this study, we investigated the role of PRMT5 in human acute myeloid leukemia (AML). Using an enzymatic dead version of PRMT5 and a PRMT5-specific inhibitor, we demonstrated the requirement of the catalytic activity of PRMT5 for the survival of AML cells. We then identified PRMT5 substrates using multiplexed quantitative proteomics and investigated their role in the survival of AML cells. We found that the function of the splicing regulator SRSF1 relies on its methylation by PRMT5 and that loss of PRMT5 leads to changes in alternative splicing of multiple essential genes. Our study proposes a mechanism for the requirement of PRMT5 for leukemia cell survival and provides potential biomarkers for the treatment response to PRMT5 inhibitors.

AB - Protein arginine methyltransferase 5 (PRMT5) has emerged as a promising cancer drug target, and three PRMT5 inhibitors are currently in clinical trials for multiple malignancies. In this study, we investigated the role of PRMT5 in human acute myeloid leukemia (AML). Using an enzymatic dead version of PRMT5 and a PRMT5-specific inhibitor, we demonstrated the requirement of the catalytic activity of PRMT5 for the survival of AML cells. We then identified PRMT5 substrates using multiplexed quantitative proteomics and investigated their role in the survival of AML cells. We found that the function of the splicing regulator SRSF1 relies on its methylation by PRMT5 and that loss of PRMT5 leads to changes in alternative splicing of multiple essential genes. Our study proposes a mechanism for the requirement of PRMT5 for leukemia cell survival and provides potential biomarkers for the treatment response to PRMT5 inhibitors.

U2 - 10.1038/s41594-019-0313-z

DO - 10.1038/s41594-019-0313-z

M3 - Journal article

C2 - 31611688

SN - 1545-9993

VL - 26

SP - 999

EP - 1012

JO - Nature Structural & Molecular Biology

JF - Nature Structural & Molecular Biology

IS - 11

ER -

PRMT5 methylome profiling uncovers a direct link to splicing regulation in acute myeloid leukemia

Abstract

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