Therapeutic Targeting of RNA Splicing Catalysis through Inhibition of Protein Arginine Methylation

Jia Yi Fong; Luca Pignata; Pierre Alexis Goy; Kimihito Cojin Kawabata; Stanley Chun Wei Lee; Cheryl M. Koh; Daniele Musiani; Enrico Massignani; Andriana G. Kotini; Alex Penson; Cheng Mun Wun; Y. Shen; M. Schwarz; Diana HP Low; Alexander Rialdi; Michelle Ki; H. Wollmann; Slim Mzoughi; Florence Gay; Christine Thompson; Timothy Hart; O. Barbash; Genna M. Luciani; Magdalena M. Szewczyk; B. J. Wouters; Ruud Delwel; Eirini P. Papapetrou; D. Barsyte-Lovejoy; Cheryl H. Arrowsmith; Mark D. Minden; Jian Jin; Ari Melnick; Tiziana Bonaldi; Omar Abdel-Wahab; Ernesto Guccione

doi:10.1016/j.ccell.2019.07.003

Therapeutic Targeting of RNA Splicing Catalysis through Inhibition of Protein Arginine Methylation

Jia Yi Fong, Luca Pignata, Pierre Alexis Goy, Kimihito Cojin Kawabata, Stanley Chun Wei Lee, Cheryl M. Koh, Daniele Musiani, Enrico Massignani, Andriana G. Kotini, Alex Penson, Cheng Mun Wun, Y. Shen, M. Schwarz, Diana HP Low, Alexander Rialdi, Michelle Ki, H. Wollmann, Slim Mzoughi, Florence Gay, Christine ThompsonTimothy Hart, O. Barbash, Genna M. Luciani, Magdalena M. Szewczyk, B. J. Wouters, Ruud Delwel, Eirini P. Papapetrou, D. Barsyte-Lovejoy, Cheryl H. Arrowsmith, Mark D. Minden, Jian Jin, Ari Melnick, Tiziana Bonaldi, Omar Abdel-Wahab, Ernesto Guccione

Istituto Europeo di Oncologia

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

Abstract

Cancer-associated mutations in genes encoding RNA splicing factors (SFs) commonly occur in leukemias, as well as in a variety of solid tumors, and confer dependence on wild-type splicing. These observations have led to clinical efforts to directly inhibit the spliceosome in patients with refractory leukemias. Here, we identify that inhibiting symmetric or asymmetric dimethylation of arginine, mediated by PRMT5 and type I protein arginine methyltransferases (PRMTs), respectively, reduces splicing fidelity and results in preferential killing of SF-mutant leukemias over wild-type counterparts. These data identify genetic subsets of cancer most likely to respond to PRMT inhibition, synergistic effects of combined PRMT5 and type I PRMT inhibition, and a mechanistic basis for the therapeutic efficacy of PRMT inhibition in cancer. Fong et al. show that spliceosomal mutant leukemias are preferentially sensitive to inhibition of protein arginine methyltransferases (PRMTs), that RNA-binding proteins are enriched among substrates of PRMT5 and type I PRMTs, and that combined PRMT5 and type I PRMT inhibition synergistically kill these leukemia cells.

Original language	English
Pages (from-to)	194-209.e9
Journal	Cancer Cell
Volume	36
Issue number	2
DOIs	https://doi.org/10.1016/j.ccell.2019.07.003
Publication status	Published - Aug 12 2019

Keywords

AML
Arginine methylation
MDS
MS023
PRMT1
PRMT5
SF3B1
Splicing factor mutations
SRSF2
U2AF1

ASJC Scopus subject areas

Oncology
Cell Biology
Cancer Research

Access to Document

10.1016/j.ccell.2019.07.003

Cite this

Fong, J. Y., Pignata, L., Goy, P. A., Kawabata, K. C., Lee, S. C. W., Koh, C. M., Musiani, D., Massignani, E., Kotini, A. G., Penson, A., Wun, C. M., Shen, Y., Schwarz, M., Low, D. HP., Rialdi, A., Ki, M., Wollmann, H., Mzoughi, S., Gay, F., ... Guccione, E. (2019). Therapeutic Targeting of RNA Splicing Catalysis through Inhibition of Protein Arginine Methylation. Cancer Cell, 36(2), 194-209.e9. https://doi.org/10.1016/j.ccell.2019.07.003

Therapeutic Targeting of RNA Splicing Catalysis through Inhibition of Protein Arginine Methylation. / Fong, Jia Yi; Pignata, Luca; Goy, Pierre Alexis; Kawabata, Kimihito Cojin; Lee, Stanley Chun Wei; Koh, Cheryl M.; Musiani, Daniele; Massignani, Enrico; Kotini, Andriana G.; Penson, Alex; Wun, Cheng Mun; Shen, Y.; Schwarz, M.; Low, Diana HP; Rialdi, Alexander; Ki, Michelle; Wollmann, H.; Mzoughi, Slim; Gay, Florence; Thompson, Christine; Hart, Timothy; Barbash, O.; Luciani, Genna M.; Szewczyk, Magdalena M.; Wouters, B. J.; Delwel, Ruud; Papapetrou, Eirini P.; Barsyte-Lovejoy, D.; Arrowsmith, Cheryl H.; Minden, Mark D.; Jin, Jian; Melnick, Ari; Bonaldi, Tiziana; Abdel-Wahab, Omar; Guccione, Ernesto.

In: Cancer Cell, Vol. 36, No. 2, 12.08.2019, p. 194-209.e9.

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

Fong, JY, Pignata, L, Goy, PA, Kawabata, KC, Lee, SCW, Koh, CM, Musiani, D, Massignani, E, Kotini, AG, Penson, A, Wun, CM, Shen, Y, Schwarz, M, Low, DHP, Rialdi, A, Ki, M, Wollmann, H, Mzoughi, S, Gay, F, Thompson, C, Hart, T, Barbash, O, Luciani, GM, Szewczyk, MM, Wouters, BJ, Delwel, R, Papapetrou, EP, Barsyte-Lovejoy, D, Arrowsmith, CH, Minden, MD, Jin, J, Melnick, A, Bonaldi, T, Abdel-Wahab, O & Guccione, E 2019, 'Therapeutic Targeting of RNA Splicing Catalysis through Inhibition of Protein Arginine Methylation', Cancer Cell, vol. 36, no. 2, pp. 194-209.e9. https://doi.org/10.1016/j.ccell.2019.07.003

Fong, Jia Yi ; Pignata, Luca ; Goy, Pierre Alexis ; Kawabata, Kimihito Cojin ; Lee, Stanley Chun Wei ; Koh, Cheryl M. ; Musiani, Daniele ; Massignani, Enrico ; Kotini, Andriana G. ; Penson, Alex ; Wun, Cheng Mun ; Shen, Y. ; Schwarz, M. ; Low, Diana HP ; Rialdi, Alexander ; Ki, Michelle ; Wollmann, H. ; Mzoughi, Slim ; Gay, Florence ; Thompson, Christine ; Hart, Timothy ; Barbash, O. ; Luciani, Genna M. ; Szewczyk, Magdalena M. ; Wouters, B. J. ; Delwel, Ruud ; Papapetrou, Eirini P. ; Barsyte-Lovejoy, D. ; Arrowsmith, Cheryl H. ; Minden, Mark D. ; Jin, Jian ; Melnick, Ari ; Bonaldi, Tiziana ; Abdel-Wahab, Omar ; Guccione, Ernesto. / Therapeutic Targeting of RNA Splicing Catalysis through Inhibition of Protein Arginine Methylation. In: Cancer Cell. 2019 ; Vol. 36, No. 2. pp. 194-209.e9.

@article{d4053c8480b34672b2201a20fbfd99fb,

title = "Therapeutic Targeting of RNA Splicing Catalysis through Inhibition of Protein Arginine Methylation",

abstract = "Cancer-associated mutations in genes encoding RNA splicing factors (SFs) commonly occur in leukemias, as well as in a variety of solid tumors, and confer dependence on wild-type splicing. These observations have led to clinical efforts to directly inhibit the spliceosome in patients with refractory leukemias. Here, we identify that inhibiting symmetric or asymmetric dimethylation of arginine, mediated by PRMT5 and type I protein arginine methyltransferases (PRMTs), respectively, reduces splicing fidelity and results in preferential killing of SF-mutant leukemias over wild-type counterparts. These data identify genetic subsets of cancer most likely to respond to PRMT inhibition, synergistic effects of combined PRMT5 and type I PRMT inhibition, and a mechanistic basis for the therapeutic efficacy of PRMT inhibition in cancer. Fong et al. show that spliceosomal mutant leukemias are preferentially sensitive to inhibition of protein arginine methyltransferases (PRMTs), that RNA-binding proteins are enriched among substrates of PRMT5 and type I PRMTs, and that combined PRMT5 and type I PRMT inhibition synergistically kill these leukemia cells.",

keywords = "AML, Arginine methylation, MDS, MS023, PRMT1, PRMT5, SF3B1, Splicing factor mutations, SRSF2, U2AF1",

author = "Fong, {Jia Yi} and Luca Pignata and Goy, {Pierre Alexis} and Kawabata, {Kimihito Cojin} and Lee, {Stanley Chun Wei} and Koh, {Cheryl M.} and Daniele Musiani and Enrico Massignani and Kotini, {Andriana G.} and Alex Penson and Wun, {Cheng Mun} and Y. Shen and M. Schwarz and Low, {Diana HP} and Alexander Rialdi and Michelle Ki and H. Wollmann and Slim Mzoughi and Florence Gay and Christine Thompson and Timothy Hart and O. Barbash and Luciani, {Genna M.} and Szewczyk, {Magdalena M.} and Wouters, {B. J.} and Ruud Delwel and Papapetrou, {Eirini P.} and D. Barsyte-Lovejoy and Arrowsmith, {Cheryl H.} and Minden, {Mark D.} and Jian Jin and Ari Melnick and Tiziana Bonaldi and Omar Abdel-Wahab and Ernesto Guccione",

year = "2019",

month = aug,

day = "12",

doi = "10.1016/j.ccell.2019.07.003",

language = "English",

volume = "36",

pages = "194--209.e9",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "2",

}

TY - JOUR

T1 - Therapeutic Targeting of RNA Splicing Catalysis through Inhibition of Protein Arginine Methylation

AU - Fong, Jia Yi

AU - Pignata, Luca

AU - Goy, Pierre Alexis

AU - Kawabata, Kimihito Cojin

AU - Lee, Stanley Chun Wei

AU - Koh, Cheryl M.

AU - Musiani, Daniele

AU - Massignani, Enrico

AU - Kotini, Andriana G.

AU - Penson, Alex

AU - Wun, Cheng Mun

AU - Shen, Y.

AU - Schwarz, M.

AU - Low, Diana HP

AU - Rialdi, Alexander

AU - Ki, Michelle

AU - Wollmann, H.

AU - Mzoughi, Slim

AU - Gay, Florence

AU - Thompson, Christine

AU - Hart, Timothy

AU - Barbash, O.

AU - Luciani, Genna M.

AU - Szewczyk, Magdalena M.

AU - Wouters, B. J.

AU - Delwel, Ruud

AU - Papapetrou, Eirini P.

AU - Barsyte-Lovejoy, D.

AU - Arrowsmith, Cheryl H.

AU - Minden, Mark D.

AU - Jin, Jian

AU - Melnick, Ari

AU - Bonaldi, Tiziana

AU - Abdel-Wahab, Omar

AU - Guccione, Ernesto

PY - 2019/8/12

Y1 - 2019/8/12

N2 - Cancer-associated mutations in genes encoding RNA splicing factors (SFs) commonly occur in leukemias, as well as in a variety of solid tumors, and confer dependence on wild-type splicing. These observations have led to clinical efforts to directly inhibit the spliceosome in patients with refractory leukemias. Here, we identify that inhibiting symmetric or asymmetric dimethylation of arginine, mediated by PRMT5 and type I protein arginine methyltransferases (PRMTs), respectively, reduces splicing fidelity and results in preferential killing of SF-mutant leukemias over wild-type counterparts. These data identify genetic subsets of cancer most likely to respond to PRMT inhibition, synergistic effects of combined PRMT5 and type I PRMT inhibition, and a mechanistic basis for the therapeutic efficacy of PRMT inhibition in cancer. Fong et al. show that spliceosomal mutant leukemias are preferentially sensitive to inhibition of protein arginine methyltransferases (PRMTs), that RNA-binding proteins are enriched among substrates of PRMT5 and type I PRMTs, and that combined PRMT5 and type I PRMT inhibition synergistically kill these leukemia cells.

AB - Cancer-associated mutations in genes encoding RNA splicing factors (SFs) commonly occur in leukemias, as well as in a variety of solid tumors, and confer dependence on wild-type splicing. These observations have led to clinical efforts to directly inhibit the spliceosome in patients with refractory leukemias. Here, we identify that inhibiting symmetric or asymmetric dimethylation of arginine, mediated by PRMT5 and type I protein arginine methyltransferases (PRMTs), respectively, reduces splicing fidelity and results in preferential killing of SF-mutant leukemias over wild-type counterparts. These data identify genetic subsets of cancer most likely to respond to PRMT inhibition, synergistic effects of combined PRMT5 and type I PRMT inhibition, and a mechanistic basis for the therapeutic efficacy of PRMT inhibition in cancer. Fong et al. show that spliceosomal mutant leukemias are preferentially sensitive to inhibition of protein arginine methyltransferases (PRMTs), that RNA-binding proteins are enriched among substrates of PRMT5 and type I PRMTs, and that combined PRMT5 and type I PRMT inhibition synergistically kill these leukemia cells.

KW - AML

KW - Arginine methylation

KW - MDS

KW - MS023

KW - PRMT1

KW - PRMT5

KW - SF3B1

KW - Splicing factor mutations

KW - SRSF2

KW - U2AF1

UR - http://www.scopus.com/inward/record.url?scp=85069824657&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85069824657&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2019.07.003

DO - 10.1016/j.ccell.2019.07.003

M3 - Article

C2 - 31408619

AN - SCOPUS:85069824657

VL - 36

SP - 194-209.e9

JO - Cancer Cell

JF - Cancer Cell

SN - 1535-6108

IS - 2

ER -

Therapeutic Targeting of RNA Splicing Catalysis through Inhibition of Protein Arginine Methylation

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this