MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism

被引：205

作者：

Bandopadhayay, Pratiti ^{[1
,2
,3
,4
]}

Ramkissoon, Lori A. ^{[5
]}

Jain, Payal ^{[6
,7
,8
]}

Bergthold, Guillaume ^{[9
,10
]}

Wala, Jeremiah ^{[1
,3
,4
]}

Zeid, Rhamy ^{[4
,5
]}

Schumacher, Steven E. ^{[1
,3
]}

Urbanski, Laura ^{[1
]}

O'Rourke, Ryan ^{[1
,3
]}

Gibson, William J. ^{[1
,3
,4
]}

Pelton, Kristine ^{[5
]}

Ramkissoon, Shakti H. ^{[5
,11
,12
,13
]}

Han, Harry J. ^{[6
,7
]}

Zhu, Yuankun ^{[6
,7
]}

Choudhari, Namrata ^{[6
,7
]}

Silva, Amanda ^{[5
,6
,7
]}

Boucher, Katie ^{[6
,7
]}

Henn, Rosemary E. ^{[6
,7
]}

Kang, Yun Jee ^{[5
]}

Knoff, David ^{[5
]}

Paolella, Brenton R. ^{[1
,3
,4
]}

Gladden-Young, Adrianne ^{[14
]}

Varlet, Pascale ^{[15
]}

Pages, Melanie ^{[15
]}

Horowitz, Peleg M. ^{[1
,16
]}

Federation, Alexander ^{[4
,5
]}

Malkin, Hayley ^{[2
]}

Tracy, Adam A. ^{[3
]}

Seepo, Sara ^{[3
]}

Ducar, Matthew ^{[11
,17
]}

Van Hummelen, Paul ^{[17
]}

Santi, Mariarita ^{[18
,19
]}

Buccoliero, Anna Maria ^{[20
]}

Scagnet, Mirko ^{[21
]}

Bowers, Daniel C. ^{[22
]}

Giannini, Caterina ^{[23
]}

Puget, Stephanie ^{[24
]}

Hawkins, Cynthia ^{[25
]}

Tabori, Uri ^{[26
]}

Klekner, Almos ^{[27
]}

Bognar, Laszlo ^{[27
]}

Burger, Peter C. ^{[28
]}

Eberhart, Charles ^{[28
]}

Rodriguez, Fausto J. ^{[28
]}

Hill, D. Ashley ^{[29
,30
,31
]}

Mueller, Sabine ^{[32
,33
,34
]}

Haas-Kogan, Daphne A. ^{[33
,35
,36
]}

Phillips, Joanna J. ^{[33
,37
]}

Santagata, Sandro ^{[1
,11
,12
,13
]}

Stiles, Charles D. ^{[1
]}

机构：

[1] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA

[2] Dana Farber Boston Childrens Canc & Blood Disorde, Boston, MA USA

[3] Broad Inst, Cambridge, MA USA

[4] Harvard Univ, Sch Med, Boston, MA USA

[5] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[6] Childrens Hosp Philadelphia, Div Neurosurg, Philadelphia, PA 19104 USA

[7] Univ Penn, Perelman Sch Med, Dept Neurosurg, Philadelphia, PA 19104 USA

[8] Univ Penn, Perelman Sch Med, Gene Therapy & Vaccines Program, Cell & Mol Biol Grad Grp, Philadelphia, PA 19104 USA

[9] Univ Paris 11, Gustave Roussy, Dept Cancerol Enfant & Adolescent, Villejuif, France

[10] Univ Paris 11, Gustave Roussy, Unite Mixte Rech Ctr Natl Rech Sci Vectorol & Nou, Villejuif, France

[11] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA

[12] Boston Childrens Hosp, Dept Pathol, Boston, MA USA

[13] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA

[14] Broad Inst, Broad Technol Labs, Cambridge, MA USA

[15] Univ Paris V Descartes, Hop St Anne, Neuropathol Lab, Paris, France

[16] Brigham & Womens Hosp, Dept Neurosurg, 75 Francis St, Boston, MA 02115 USA

[17] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA

[18] Childrens Hosp Philadelphia, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA

[19] Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA

[20] Anna Meyer Childrens Univ Hosp, Pathol Unit, Florence, Italy

[21] Univ Florence, Anna Meyer Childrens Hosp, Neurosurg Unit, Florence, Italy

[22] Univ Texas Southwestern Med Sch, Div Pediat Hematol Oncol, Dallas, TX USA

[23] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA

[24] Univ Paris V Descartes, Hop Necker Enfants Malad, Dept Neurochirurg, Paris, France

[25] Hosp Sick Children, Div Pathol, 555 Univ Ave, Toronto, ON M5G 1X8, Canada

[26] Hosp Sick Children, Div Haematol Oncol, 555 Univ Ave, Toronto, ON M5G 1X8, Canada

[27] Univ Debrecen, Med & Hlth Sci Ctr, Dept Neurosurg, Debrecen, Hungary

[28] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA

[29] Childrens Natl Med Ctr, Brain Tumor Inst, Washington, DC 20010 USA

[30] Childrens Natl Med Ctr, Ctr Neurosci & Behav Med, Brain Tumor Inst, Washington, DC 20010 USA

[31] Childrens Natl Med Ctr, Dept Pathol, Washington, DC 20010 USA

[32] Univ Calif San Francisco, Sch Med, Dept Neurol, San Francisco, CA USA

[33] Univ Calif San Francisco, Sch Med, Dept Neurol Surg, San Francisco, CA USA

[34] Univ Calif San Francisco, Sch Med, Dept Pediat, San Francisco, CA 94143 USA

[35] Univ Calif San Francisco, Sch Med, Dept Radiat Oncol, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA

[36] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol,Brigham & Womens Hosp,Boston Ch, 44 Binney St, Boston, MA 02115 USA

[37] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94140 USA

[38] Harvard Univ, Sch Med, Dept Med, Boston, MA USA

[39] McGill Univ, Montreal Childrens Hosp, Div Expt Med, Montreal, PQ H3H 1P3, Canada

[40] McGill Univ, Ctr Hlth, Montreal, PQ, Canada

[41] McGill Univ, Dept Human Genet, Montreal, PQ, Canada

[42] McGill Univ, Dept Pediat, Montreal, PQ H3A 2T5, Canada

[43] Brigham & Womens Hosp, Dept Pathol, Cytogenet Div, Ctr Adv Mol Diagnost, 75 Francis St, Boston, MA 02115 USA

[44] Boston Childrens Hosp, Dept Neurosurg, Boston, MA USA

[45] Harvard Univ, Sch Med, Dept Neurosurg, Boston, MA USA

[46] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA

[47] Childrens Hosp Philadelphia, Ctr Childhood Canc Res, Philadelphia, PA 19104 USA

[48] Univ Penn, Dept Pediat, Perelman Sch Med, Philadelphia, PA 19104 USA

[49] Childrens Hosp Philadelphia, Dept Biomed & Hlth Informat, Philadelphia, PA 19104 USA

[50] Childrens Hosp Philadelphia, Ctr Data Driven Discovery Biomed, Philadelphia, PA 19104 USA

来源：

NATURE GENETICS | 2016年 / 48卷 / 03期

基金：

美国国家卫生研究院;

关键词：

BET BROMODOMAIN INHIBITION; ADENOID CYSTIC CARCINOMA; LOW-GRADE GLIOMAS; NEURAL STEM-CELL; C-MYB; V-MYB; CANCER; PROTEIN; GENE; TRANSFORMATION;

D O I：

10.1038/ng.3500

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Angiocentric gliomas are pediatric low-grade gliomas (PLGGs) without known recurrent genetic drivers. We performed genomic analysis of new and published data from 249 PLGGs, including 19 angiocentric gliomas. We identified MYB-QKI fusions as a specific and single candidate driver event in angiocentric gliomas. In vitro and in vivo functional studies show that MYB-QKI rearrangements promote tumorigenesis through three mechanisms: MYB activation by truncation, enhancer translocation driving aberrant MYB-QKI expression and hemizygous loss of the tumor suppressor QKI. To our knowledge, this represents the first example of a single driver rearrangement simultaneously transforming cells via three genetic and epigenetic mechanisms in a tumor.

引用

页码：273 / 282

页数：10

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