A novel retinoblastoma therapy from genomic and epigenetic analyses

被引：387

作者：

Zhang, Jinghui ^{[2
]}

Benavente, Claudia A. ^{[1
]}

McEvoy, Justina ^{[1
]}

Flores-Otero, Jacqueline ^{[1
]}

Ding, Li ^{[3
,4
]}

Chen, Xiang ^{[2
]}

Ulyanov, Anatoly ^{[2
]}

Wu, Gang ^{[2
]}

Wilson, Matthew ^{[5
,6
]}

Wang, Jianmin ^{[7
]}

Brennan, Rachel ^{[1
]}

Rusch, Michael ^{[2
]}

Manning, Amity L. ^{[8
]}

Ma, Jing ^{[9
]}

Easton, John ^{[2
]}

Shurtleff, Sheila ^{[9
]}

Mullighan, Charles ^{[9
]}

Pounds, Stanley ^{[10
]}

Mukatira, Suraj ^{[7
]}

Gupta, Pankaj ^{[7
]}

Neale, Geoff ^{[7
]}

Zhao, David ^{[11
]}

Lu, Charles ^{[3
]}

Fulton, Robert S. ^{[3
,4
]}

Fulton, Lucinda L. ^{[3
,4
]}

Hong, Xin ^{[3
,4
]}

Dooling, David J. ^{[3
,4
]}

Ochoa, Kerri ^{[3
,4
]}

Naeve, Clayton ^{[11
]}

Dyson, Nicholas J. ^{[8
]}

Mardis, Elaine R. ^{[3
,4
,12
]}

Bahrami, Armita ^{[9
]}

Ellison, David ^{[9
]}

Wilson, Richard K. ^{[3
,4
,13
]}

Downing, James R. ^{[9
]}

Dyer, Michael A. ^{[1
,5
,14
]}

机构：

[1] St Jude Childrens Res Hosp, Dept Dev Neurobiol, Memphis, TN 38105 USA

[2] St Jude Childrens Res Hosp, Dept Computat Biol & Bioinformat, Memphis, TN 38105 USA

[3] Washington Univ, Sch Med St Louis, Genome Inst, St Louis, MO 63108 USA

[4] Washington Univ, Sch Med St Louis, Dept Genet, St Louis, MO 63108 USA

[5] Univ Tennessee, Hlth Sci Ctr, Dept Ophthalmol, Memphis, TN 38163 USA

[6] St Jude Childrens Res Hosp, Dept Surg, Memphis, TN 38105 USA

[7] St Jude Childrens Res Hosp, Hartwell Ctr Biotechnol & Bioinformat, Memphis, TN 38105 USA

[8] Massachusetts Gen Hosp, Charlestown, MA 02129 USA

[9] St Jude Childrens Res Hosp, Dept Pathol, Memphis, TN 38105 USA

[10] St Jude Childrens Res Hosp, Dept Biostat, Memphis, TN 38105 USA

[11] St Jude Childrens Res Hosp, Dept Informat Sci, Memphis, TN 38105 USA

[12] Washington Univ, Sch Med St Louis, Siteman Canc Ctr, St Louis, MO 63108 USA

[13] Washington Univ, Sch Med St Louis, Dept Med, St Louis, MO 63108 USA

[14] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA

来源：

NATURE | 2012年 / 481卷 / 7381期

关键词：

TYROSINE KINASE; SYK INHIBITOR; CANCER; ANEUPLOIDY; GROWTH; CELLS; TUMOR; MCL-1; GENE;

D O I：

10.1038/nature10733

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Retinoblastoma is an aggressive childhood cancer of the developing retina that is initiated by the biallelic loss of RB1. Tumours progress very quickly following RB1 inactivation but the underlying mechanism is not known. Here we show that the retinoblastoma genome is stable, but that multiple cancer pathways can be epigenetically deregulated. To identify the mutations that cooperate with RB1 loss, we performed whole-genome sequencing of retinoblastomas. The overall mutational rate was very low; RB1 was the only known cancer gene mutated. We then evaluated the role of RB1 in genome stability and considered non-genetic mechanisms of cancer pathway deregulation. For example, the proto-oncogene SYK is upregulated in retinoblastoma and is required for tumour cell survival. Targeting SYK with a small-molecule inhibitor induced retinoblastoma tumour cell death in vitro and in vivo. Thus, retinoblastomas may develop quickly as a result of the epigenetic deregulation of key cancer pathways as a direct or indirect result of RB1 loss.

引用

页码：329 / 334

页数：6

共 32 条

[1] RNAi mediated acute depletion of Retinoblastoma protein (pRb) promotes aneuploidy in human primary cells via micronuclei formation [J].

Amato, Angela ;

Lentini, Laura ;

Schillaci, Tiziana ;

Iovino, Flora ;

Di Leonardo, Aldo .

BMC CELL BIOLOGY, 2009, 10 :79

[2] The tyrosine kinase Syk regulates the survival of chronic lymphocytic leukemia B cells through PKCδ and proteasome-dependent regulation of Mcl-1 expression [J].

Baudot, A. D. ;

Jeandel, P. Y. ;

Mouska, X. ;

Maurer, U. ;

Tartare-Deckert, S. ;

Raynaud, S. D. ;

Cassuto, J. P. ;

Ticchioni, M. ;

Deckert, M. .

ONCOGENE, 2009, 28 (37) :3261-3273

[3] A mammalian microRNA cluster controls DNA methylation and telomere recombination via Rbl2-dependent regulation of DNA methyltransferases (vol 15, pg 268, 2008) [J].

Benetti, Roberta ;

Gonzalo, Susana ;

Jaco, Isabel ;

Munoz, Purificacion ;

Gonzalez, Susana ;

Schoeftner, Stefan ;

Murchison, Elizabeth ;

Andl, Thomas ;

Chen, Taiping ;

Klatt, Peter ;

Li, En ;

Serrano, Manuel ;

Millar, Sarah ;

Hannon, Gregory ;

Blasco, Maria A. .

NATURE STRUCTURAL & MOLECULAR BIOLOGY, 2008, 15 (09) :998-998

[4] SWI/SNF Deficiency Results in Aberrant Chromatin Organization, Mitotic Failure, and Diminished Proliferative Capacity [J].

Bourgo, Ryan J. ;

Siddiqui, Hasan ;

Fox, Sejal ;

Solomon, David ;

Sansam, Courtney G. ;

Yaniv, Moshe ;

Muchardt, Christian ;

Metzger, Daniel ;

Chambon, Pierre ;

Roberts, Charles W. M. ;

Knudsen, Erik S. .

MOLECULAR BIOLOGY OF THE CELL, 2009, 20 (14) :3192-3199

[5] Targeting the p53 Pathway in Retinoblastoma with Subconjunctival Nutlin-3a [J].

Brennan, Rachel C. ;

Federico, Sara ;

Bradley, Cori ;

Zhang, Jiakun ;

Flores-Otero, Jacqueline ;

Wilson, Matthew ;

Stewart, Clinton ;

Zhu, Fangyi ;

Guy, Kip ;

Dyer, Michael A. .

CANCER RESEARCH, 2011, 71 (12) :4205-4213

[6] Spleen tyrosine kinase inhibition prevents chemokine- and integrin-mediated stromal protective effects in chronic lymphocytic leukemia [J].

Buchner, Maike ;

Baer, Constance ;

Prinz, Gabriele ;

Dierks, Christine ;

Burger, Meike ;

Zenz, Thorsten ;

Stilgenbauer, Stephan ;

Jumaa, Hassan ;

Veelken, Hendrik ;

Zirlik, Katja .

BLOOD, 2010, 115 (22) :4497-4506

[7] SYK-dependent tonic B-cell receptor signaling is a rational treatment target in diffuse large B-cell lymphoma [J].

Chen, Linfeng ;

Monti, Stefano ;

Juszczynski, Przemyslaw ;

Daley, John ;

Chen, Wen ;

Witzig, Thomas E. ;

Habermann, Thomas M. ;

Kutok, Jeffery L. ;

Shipp, Margaret A. .

BLOOD, 2008, 111 (04) :2230-2237

[8] Covalent histone modifications - miswritten, misinterpreted and mis-erased in human cancers [J].

Chi, Ping ;

Allis, C. David ;

Wang, Gang Greg .

NATURE REVIEWS CANCER, 2010, 10 (07) :457-469

[9] One hit, two hits, three hits, more? Genomic changes in the development of retinoblastoma [J].

Corson, Timothy W. ;

Gallie, Brenda L. .

GENES CHROMOSOMES & CANCER, 2007, 46 (07) :617-634

[10] Timeline - The history of cancer epigenetics [J].

Feinberg, AP ;

Tycko, B .

NATURE REVIEWS CANCER, 2004, 4 (02) :143-153

← 1 2 3 4 →