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 -