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

The Danish Stem Cell Center

29 Citations (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.

Original language	English
Journal	Nature Structural & Molecular Biology
Volume	26
Issue number	11
Pages (from-to)	999-1012
Number of pages	12
ISSN	1545-9993
DOIs	https://doi.org/10.1038/s41594-019-0313-z
Publication status	Published - 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.",

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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

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JO - Nature Structural & Molecular Biology

JF - Nature Structural & Molecular Biology

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ER -

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

Abstract

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