Genetic deletion or small-molecule inhibition of the arginine methyltransferase PRMT5 exhibit anti-tumoral activity in mouse models of MLL-rearranged AML

被引：67

作者：

Kaushik, S. ^{[1
]}

Liu, F. ^{[2
]}

Veazey, K. J. ^{[1
]}

Gao, G. ^{[1
]}

Das, P. ^{[1
]}

Neves, L. F. ^{[1
]}

Lin, K. ^{[1
,3
]}

Zhong, Y. ^{[1
,3
]}

Lu, Y. ^{[1
,3
]}

Giuliani, V. ^{[4
]}

Bedford, M. T. ^{[1
,3
]}

Nimer, S. D. ^{[2
,5
]}

Santos, M. A. ^{[1
,3
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Epigenet & Mol Carcinogenesis, 1515 Holcombe Blvd, Houston, TX 77030 USA

[2] Univ Miami, Miller Sch Med, Dept Biochem & Mol Biol, Sylvester Comprehens Canc Ctr, Miami, FL 33136 USA

[3] Ctr Canc Epigenet, Houston, TX USA

[4] Univ Texas MD Anderson Canc Ctr, Inst Appl Canc Sci, Ctr Coclin Trials, Houston, TX 77030 USA

[5] Univ Miami, Miller Sch Med, Dept Med, Sylvester Comprehens Canc Ctr, Miami, FL 33136 USA

来源：

LEUKEMIA | 2018年 / 32卷 / 02期

关键词：

REAL-TIME PCR; MYELOID-LEUKEMIA; FUSION PROTEINS; STEM-CELLS; IN-VITRO; METHYLATION; HISTONE; DNA; EXPRESSION; CHROMATIN;

D O I：

10.1038/leu.2017.206

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

The hematological malignancies classified as mixed lineage leukemias (MLL) harbor fusions of the MLL1 gene to partners that are members of transcriptional elongation complexes. MLL-rearranged leukemias are associated with extremely poor prognosis, and response to conventional therapies and efforts to identify molecular targets are urgently needed. Using mouse models of MLL-rearranged acute myeloid leukemia, here we show that genetic inactivation or small-molecule inhibition of the protein arginine methyltransferase PRMT5 exhibit anti-tumoral activity in MLL-fusion protein-driven transformation. Genome-wide transcriptional analysis revealed that inhibition of PRMT5 methyltransferase activity overrides the differentiation block in leukemia cells without affecting the expression of MLL-fusion direct oncogenic targets. Furthermore, we find that this differentiation block is mediated by transcriptional silencing of the cyclin-dependent kinase inhibitor p21 (CDKN1a) gene in leukemia cells. Our study provides pre-clinical rationale for targeting PRMT5 using small-molecule inhibitors in the treatment of leukemias harboring MLL rearrangements.

引用

页码：499 / 509

页数：11

共 56 条

[1] Nuclear Cyclin D1/CDK4 Kinase Regulates CUL4 Expression and Triggers Neoplastic Growth via Activation of the PRMT5 Methyltransferase [J].

Aggarwal, Priya ;

Vaites, Laura Pontano ;

Kim, Jong Kyong ;

Mellert, Hestia ;

Gurung, Buddha ;

Nakagawa, Hiroshi ;

Herlyn, Meenhard ;

Hua, Xianxin ;

Rustgi, Anil K. ;

McMahon, Steven B. ;

Diehl, J. Alan .

CANCER CELL, 2010, 18 (04) :329-340

[2] Differential expression analysis for sequence count data [J].

Anders, Simon ;

Huber, Wolfgang .

GENOME BIOLOGY, 2010, 11 (10)

[3] HTSeq-a Python']Python framework to work with high-throughput sequencing data [J].

Anders, Simon ;

Pyl, Paul Theodor ;

Huber, Wolfgang .

BIOINFORMATICS, 2015, 31 (02) :166-169

[4] Protein Arginine Methyltransferase 5 Regulates ERK1/2 Signal Transduction Amplitude and Cell Fate Through CRAF [J].

Andreu-Perez, Pedro ;

Esteve-Puig, Rosaura ;

de Torre-Minguela, Carlos ;

Lopez-Fauqued, Marta ;

Josep Bech-Serra, Joan ;

Tenbaum, Stephan ;

Garcia-Trevijano, Elena R. ;

Canals, Francesc ;

Merlino, Glenn ;

Avila, Matias A. ;

Recio, Juan A. .

SCIENCE SIGNALING, 2011, 4 (190)

[5] Arginine methylation: An emerging regulator of protein function [J].

Bedford, MT ;

Richard, S .

MOLECULAR CELL, 2005, 18 (03) :263-272

[6] Targeting Epigenetic Programs in MLL-Rearranged Leukemias [J].

Bernt, Kathrin M. ;

Armstrong, Scott A. .

HEMATOLOGY-AMERICAN SOCIETY HEMATOLOGY EDUCATION PROGRAM, 2011, :354-360

[7] MLL-Rearranged Leukemia Is Dependent on Aberrant H3K79 Methylation by DOT1L [J].

Bernt, Kathrin M. ;

Zhu, Nan ;

Sinha, Amit U. ;

Vempati, Sridhar ;

Faber, Joerg ;

Krivtsov, Andrei V. ;

Feng, Zhaohui ;

Punt, Natalie ;

Daigle, Amanda ;

Bullinger, Lars ;

Pollock, Roy M. ;

Richon, Victoria M. ;

Kung, Andrew L. ;

Armstrong, Scott A. .

CANCER CELL, 2011, 20 (01) :66-78

[8]

Chan-Penebre E, 2015, NAT CHEM BIOL, V11, P432, DOI [10.1038/NCHEMBIO.1810, 10.1038/nchembio.1810]

[9] A TGFβ-PRMT5-MEP50 axis regulates cancer cell invasion through histone H3 and H4 arginine methylation coupled transcriptional activation and repression [J].

Chen, H. ;

Lorton, B. ;

Gupta, V. ;

Shechter, D. .

ONCOGENE, 2017, 36 (03) :373-386

[10] Protein arginine-methyltransferase-dependent oncogenesis [J].

Cheung, Ngai ;

Chan, Li Chong ;

Thompson, Alex ;

Cleary, Michael L. ;

So, Chi Wai Eric .

NATURE CELL BIOLOGY, 2007, 9 (10) :1208-1215

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